Foamable Vehicle and Pharmaceutical Compositions Thereof

ABSTRACT

A hygroscopic pharmaceutical composition includes at least one hygroscopic substance at a concentration sufficient to provide an Aw value of at least 0.9 and an antiinfective agent. A foamble pharmaceutical carrier includes about 50% to about 98% of a polar solvent selected from the group consisting of a polyol and PEG; 0% to about 48% of a secondary polar solvent; about 0.2% to about 5% by weight of a surface-active agent; about 0.01% to about 5% by weight of at least one polymeric agent; and a liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/708,284, filed on Dec. 7, 2012, which is a continuation of U.S.patent application Ser. No. 12/767,511, filed on Apr. 26, 2010, which isa continuation of and claims the benefit of priority under 35 U.S.C.§120 to U.S. patent application Ser. No. 11/430,599, filed on May 9,2006, now U.S. Pat. No. 7,704,518, which claims the benefit under 35U.S.C. §119(e) of U.S. Provisional Patent Application No. 60/679,020,filed on May 9, 2005, and of U.S. Provisional Patent Application No.60/784,793, filed on Mar. 21, 2006, and which is a continuation-in-partapplication of co-pending U.S. patent application Ser. No. 10/835,505,filed on Apr. 28, 2004, now U.S. Pat. No. 7,820,145, which claims thebenefit of priority under 35 U.S.C. §119(e) to U.S. Patent ApplicationSer. No. 60/530,015, filed on Dec. 16, 2003, and U.S. Patent ApplicationSer. No. 60/492,385, filed on Aug. 4, 2003, all of which are herebyincorporated in their entirety by reference.

BACKGROUND OF THE INVENTION

This invention relates to foamable pharmaceutical and cosmeticcompositions.

External topical administration is an important route for theadministration of drugs in disease treatment. Many groups of drugs,including, for example, antibiotic, anti-fungal, anti-inflammatory,anesthetic, analgesic, anti-allergic, corticosteroid, retinoid andanti-proliferative medications are preferably administered inhydrophobic media, namely ointment. However, ointments often form animpermeable barrier, so that metabolic products and excreta from thewounds to which they are applied are not easily removed or drained away.Furthermore, it is difficult for the active drug dissolved in thecarrier to pass through the white petrolatum barrier layer into thewound tissue, so the efficacy of the drug is reduced. In addition,ointments and creams often do not create an environment for promotingrespiration of the wound tissue and it is not favorable to the normalrespiration of the skin. An additional disadvantage of petroleumjelly-based products relates to the greasy feeling left following theirtopical application onto the skin, mucosal membranes and wounds.

Foams and, in particular, foams that are substantially based onnon-aqueous solvents are complicated systems which do not form under allcircumstances. US Pat. Appl. No. 20050031547 relates to stableoleaginous cosmetic or therapeutic foam compositions containing certainactive agents, having unique therapeutic properties and methods oftreatment using such compositions. The foamable carrier includes atleast one solvent selected from a hydrophobic solvent, a silicone oil,an emollient, a co-solvent, and mixtures thereof, wherein the solvent ispresent at a concentration of about 70% to about 96.5% by weight of thetotal composition, at least a non-ionic surface-active agent at aconcentration of about 0.1% to less than about 0%/o by weight of thetotal composition; at least one gelling agent at a concentration ofabout 0.1% to about 5% by weight of the total composition; atherapeutically effective amount of at least one active agent; and atleast one liquefied or compressed gas propellant, at a concentration ofabout 3% to about 25% by weight of the total composition.

WO 00/09082 teaches an anhydrous cleansing composition for topicalapplication to human skin, comprising an ionic surfactant, glycerine,propylene glycol and water insoluble benefit agents. According to theexamples of WO 00/09082, the concentration of the ionic surfactant is inthe range of 18-22%.

U.S. Pat. No. 6,765,001 comprises a composition, method of enhancingpotency and method of delivering corticosteroids in a vehicle comprisingtwo or more penetration enhancers selected from the group consisting ofdiisopropyl adipate, dimethyl isosorbide, propylene glycol,1,2,6-hexapetriol, and benzyl alcohol; and one or more of the groupconsisting of solvents and emulsifiers.

WO91/11991 teaches an essentially non-aqueous and non-oily foamablecomposition, that can be used for rectal administration ofpharmaceuticals, comprising a liquid polar polyol or polyol mixture, apharmaceutically active ingredient and at least one foam stabilizing andemulsifying surfactant. However, this foam composition is associatedwith disadvantages and the purposes of the present invention are notattained (see comparative example below).

There remains an unmet need for improved, easy to use, stable andnon-irritating anti-infective foam formulations, intended for treatmentof dermal and mucosal tissues. Particularly, there remains an unmet needfor improved, easy to use, stable and non-irritating anti-infective foamformulations, with unique therapeutic properties.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a hygroscopic pharmaceuticalcomposition including at least one hygroscopic substance at a sufficientconcentration to provide an Aw value of the hygroscopic pharmaceuticalcomposition of less than 0.9 and an anti-infective agent; or the Awvalue is in the range of about 0.8 and about 0.9; (2) about 0.7 andabout 0.8; and (3) less than about 0.7

In one or more embodiments, the hygroscopic pharmaceutical compositionfurther includes at least one component, selected from the groupconsisting of about 0.01% to about 5% by weight of at least onepolymeric agent selected from a bioadhesive agent, a gelling agent, afilm forming agent and a phase change agent; and about 0.2% to about 5%by weight of a surface-active agent.

In one or more embodiments, the hygroscopic substance is selected fromthe group consisting of polyethylene glycols (PEGs), surfactantscomprising PEG, polyols, monosaccharides, disaccharides,oligosaccharides and sugar alcohols in an amount to provide hygroscopicproperties, and honey.

In another aspect, the invention provides a foamble pharmaceuticalcarrier including about 50% to about 98% of a polar solvent selectedfrom the group consisting of (1) a polyol and (2) a polyethylene glycol(PEG); 0% to about 48% of a secondary polar solvent; about 0.2% to about5% by weight of a surface-active agent; about 0.01% to about 5% byweight of at least one polymeric agent; and a liquefied or compressedgas propellant at a concentration of about 3% to about 25% by weight ofthe total composition.

In one or more embodiments, the compositions further comprise up to 10%of water.

In one or more embodiments, the composition is substantially non-aqueousand/or substantially alcohol-free.

In one or more embodiments, the composition further comprises atherapeutically effective concentration of one or more active agents.

In one or more embodiments, the polyol is selected from the groupconsisting of a diol, a triol and a saccharide, and the triol may beselected from the group consisting of glycerin, butane-1,2,3-triol,butane-1,2,4-triol and hexane-1,2,6-triol, or the diol is selected fromthe group consisting of propylene glycol, butanediol, butenediol,butynediol, pentanediol, hexanediol, octanediol, neopentyl glycol,2-methyl-1,3-propanediol, diethylene glycol, triethylene glycol,tetraethylene glycol, dipropylene glycol and dibutylene glycol.

In one or more embodiments, the polyol consists of at least one diol andat least one triol, and wherein the ratio between the diol and triol isbetween 9:1 and 1:1.

In one or more embodiments, the composition includes a mixture of atleast one polyol and at least one PEG, and the PEG may be selected fromthe group consisting of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000,PEG 4000, PEG 6000 and PEG 8000, or the composition contains one or morePEGs in a concentration to provide viscosity of less than 12,000 CPs.

In one or more embodiments, the composition includes a secondary polarsolvent selected from the group consisting of dimethyl isosorbide,tetrahydrofurfuryl alcohol polyethyleneglycol, ether, DMSO, apyrrolidone, N-Methyl-2-pyrrolidone, 1-Methyl-2-pyrrolidinone, ethylproxitol, dimethylacetamide, a PEG-type surfactant, an alpha hydroxyacid, lactic acid and glycolic acid, or the secondary polar solvent isdimethyl isosorbide.

In one or more embodiments, the composition includes (1) at least onepolar solvent selected from a diol, a triol and PEG, and (2) at leastone secondary polar solvent, and for example, the polar solventcomprises a mixture of at least one polyol and at least one PEG, and forexample, the polyol comprises a mixture of at least two polyols.

In one or more embodiments, the ratio between the polyol and/or PEG andthe secondary polar solvent is between 9:1 and 1:1.

In another aspect of the invention, a method of treating a disorder ofmammalian subject includes administering a foamable therapeuticcomposition to a target area, the composition comprising atherapeutically effective concentration of an active agent, about 50% toabout 98% of a polar solvent selected from the group consisting of (1) apolyol; and (2) a polyethylene glycol; 0% to about 48% of a secondarypolar solvent; about 0.2% to about 5% by weight of a surface-activeagent; about 0.01% to about 5% by weight of at least one polymericagent; and a liquefied or compressed gas propellant at a concentrationof about 3% to about 25% by weight of the total composition.

In one or more embodiments, the target site is selected from the groupconsisting of the skin, a body cavity, a mucosal surface, the nose, themouth, the eye, the ear canal, the respiratory system, the vagina andthe rectum.

BRIEF DESCRIPTION OF THE DRAWINGS

Various objects, features, and advantages of the present invention canbe more fully appreciated with reference to the following detaileddescription of the invention when considered in connection with thefollowing drawings, in which like reference numerals identify likeelements. The following drawings are for the purpose of illustrationonly and are not intended to be limiting of the invention, the scope ofwhich is set forth in the claims that follow.

FIG. 1A-D illustrates the in vitro effect of effect of Composition A,consisting of 2% terbinafine, 95.3% gr. polyethylene glycol, 0.5%hydroxypropyl cellulose and 2.2% steareth-2, in comparison withComposition B (an oil in water emulsion containing 2% terbinafine) andComposition C a commercial 1% bifonazole cream, in the treatment ofthree fungal strains (microsporum canis, trichophyton mentagrophytes andtrichophyton rubrum) and one yeast (candida albicans).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a composition for use as foamablevehicle composition.

According to one or more embodiments of the present invention, thefoamable carrier, includes:

-   -   a. about 50% to about 98% of a polar solvent selected from the        group consisting of (1) a polyol; and (2) a polyethylene glycol;    -   b. 0% to about 48% of a secondary polar solvent;    -   c. about 0.2% to about 5% by weight of a surface-active agent;    -   d. about 0.01% to about 5% by weight of at least one polymeric        agent; and    -   e. a liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition.        All % values are provided on a weight (w/w) basis.

Water, up to 25% of the composition, and more preferably up to 10%, andoptional ingredients are added to complete the total mass to 100%. Incertain cases, the composition contains two active agents that requiredifferent pH environments in order to remain stable. For example,corticosteroids are typically stable at acidic pH (they have a maximumstability at a pH of about 4-6) and vitamin D analogues are typicallystable at basic pH (they have a maximum stability at pH values aboveabout 8). In other cases, the active agent degrades in the presence ofwater, and therefore, in such cases the present of water in thecomposition is not desirable. Thus, in certain preferred embodiments,the composition is substantially non-aqueous. The term “substantiallynon-aqueous” is intended to indicate that the composition has a watercontent below about 5%, preferably below about 2%, such as below about1.5%.

Upon release from an aerosol container, the foamable carrier forms anexpanded foam suitable for the treatment of an infected surface and fortopical administration to the skin, a body surface, a body cavity or amucosal surface.

The identification of a “polar solvent”, as used herein, is not intendedto characterize the solubilization capabilities of the solvent for anyspecific active agent or any other component of the foamablecomposition. Rather, such information is provided to aid in theidentification of materials suitable for use as a part in the foamablecompositions described herein.

Polyol

In an embodiment of the present invention, the polar solvent is apolyol. A polyol is an organic substance that contains at least twohydroxy groups in its molecular structure.

In one or more embodiments, the foamable carrier contains at least onediol (a compound that contains two hydroxy groups in its molecularstructure). Examples of diols include propylene glycol (e.g.,1,2-propylene glycol and 1,3-propylene glycol), butanediol (e.g.,1,2-butanediol, 1,3-butanediol, 2,3-butanediol and 1,4-butanediol),butanediol (e.g., 1,3-butanediol and 1,4-butenediol), butynediol,pentanediol (e.g., pentane-1,2-diol, pentane-1,3-diol, pentane-1,4-diol,pentane-1,5-diol, pentane-2,3-diol and pentane-2,4-diol), hexanediol(e.g., hexane-1,6-diol hexane-2,3-diol and hexane-2,56-diol), octanediol(e.g., 1,8-octanediol), neopentyl glycol, 2-methyl-1,3-propanediol,diethylene glycol, triethylene glycol, tetraethylene glycol, dipropyleneglycol and dibutylene glycol.

In one or more embodiments, the foamable carrier contains at least onetriol (a compound that contains three hydroxy groups in its molecularstructure), such as glycerin, butane-1,2,3-triol, butane-1,2,4-triol andhexane-1,2,6-triol.

In one or more embodiments, the polyol is a mixture of polyols. In oneor more embodiments, the mixture of polyols contains at least one dioland at least one triol. According to certain embodiments the ratiobetween the diol and triol is between 9:1 and 1:1.

In one or more embodiments, part of mixture of polyols is a saccharide.Exemplary saccharides include, but are not limited to monosaccharide,disaccharides, oligosaccharides and sugar alcohols.

A monosaccharide is a simple sugar that cannot be hydrolysed to smallerunits. Empirical formula is (CH2O)n and range in size from trioses (n=3)to heptoses (n=7). Exemplary monosaccharide compounds are ribose,glucose, fructose and galactose.

Disaccharides are made up of two monosaccharides joined together, suchas sucrose, maltose and lactose.

A sugar alcohol (also known as a polyol, polyhydric alcohol, orpolyalcohol) is a hydrogenated form of saccharide, whose carbonyl group(aldehyde or ketone, reducing sugar) has been reduced to a primary orsecondary hydroxyl group. They are commonly used for replacing sucrosein foodstuffs, often in combination with high intensity artificialsweeteners to counter the low sweetness. Some exemplary sugar alcohols,which are suitable for use according to the present invention aremannitol, sorbitol, xylitol, maltitol, lactitol. (Maltitol and lactitolare not completely hydrogenated compounds—they are a monosaccharidecombined with a polyhydric alcohol). Mixtures of polyols, including (1)at least one polyol selected from a diol and a triol; and (2) asaccharide are contemplated within the scope of the present invention.

Polyethylene Glycol

In an embodiment of the present invention, the polar solvent consists ofa polymerized ethylene glycol, namely polyethylene glycol, which is alsotermed “PEG”. Exemplary PEGs are provided in the following table.

Composition Av. Molecular weight Appearance Melting point (° C.) PEG 200190~210 Oily liquid PEG 300 285~315 Oily liquid PEG 400 380~420 Oilyliquid PEG 600 570~630 Oily liquid 17~22 PEG 1000  950~1050 Solid 35~40PEG 4000 3800~4400 Solid 53~58 PEG 6000 5600~6400 Solid 55~60 PEG 80007500~8500 Solid 58~65

Thus, in an embodiment of the present invention, the PEG is selectedfrom the group consisting of PEG 200, PEG 300, PEG 400, PEG 600, PEG1000, PEG 4000, PEG 6000 and PEG 8000. The foamable carrier according tothe present invention can contain a single PEG or a mixture of two ormore PEGs. PEGs having molecular weight of more that about 1000 possessgelling properties; i.e., they increase the viscosity of a composition.Therefore, by combining PEGs with different molecular weights/meltingpoints, one can attain varying levels of flowability as desirable forthe treatment of a given target site. The concentration of the PEGshould be in a level that results in viscosity, prior to filling of thecomposition into aerosol canisters, of less than 12,000 CPs, and morepreferably, less than 10,000 CPs.

Secondary Polar Solvent

Optionally, a secondary polar solvent is added to the foamablecomposition of the present invention. The secondary polar solvent isselected from a variety of organic solvents that are typically miscibleon both water and oil. Examples of polar solvent that can be containedin the foamable carrier of the present invention include dimethylisosorbide, tetrahydrofurfuryl alcohol polyethyleneglycol ether(glycofurol), DMSO, pyrrolidones, (such as N-Methyl-2-pyrrolidone and1-Methyl-2-pyrrolidinone), ethyl proxitol, dimethylacetamide (DMAc),PEG-type surfactants and alpha hydroxy acids, such as lactic acid andglycolic acid.

Solubilization and Penetration Enhancement

In many cases, polyols, PEGs and polar solvents possess a highsolubilizing power and thus, they can enable increased concentrations ofa pharmaceutical active agent. Polyols, PEGs and polar solvents are alsoknown for their skin penetration enhancement properties. Theseproperties enable high drug bioavailability in the target area oftreatment, resulting in an enhanced therapeutic effect. Occasionally,combinations of a polyol, PEGs and a secondary polar solvent, exhibit anincreased permeability across the skin, as suggested, for example, inEur J Pharm Biopharm. 1998 November; 46(3):265-71.

Thus, in one or more embodiments, the foamable carrier contains (1) atleast one polar solvent, selected from a polyol (selected from a dioland a triol) and PEG; and (2) at least one secondary polar solvent.

In one or more embodiments, the foamable carrier contains (1) a mixtureof at least two polyols; and (2) at least one secondary polar solvent.In additional embodiments, the foamable carrier contains a mixture of atleast one polyol and at least one PEG; yet in other embodiments thefoamable carrier contains (1) a mixture of at least one polyol and atleast one PEG and (2) at least one secondary polar solvent.

According to certain embodiments the ratio between the polyol and/or PEGand the secondary polar solvent is between 9:1 and 1:1.

In certain embodiments, the polyol is selected from the group consistingof propylene glycol, hexylene glycol and glycerin (and mixturesthereof); and the secondary polar solvent is selected from the groupconsisting of dimethyl isosorbide, diethylene glycol monoethyl ether, aliquid polyethylene glycol and glycofurol.

In certain embodiments, the foamable carrier contains (1) at least onepolyol; and (2) dimethyl isosorbide.

Short chain alcohols, such as ethanol and propanol are known as polarsolvents, however, according to one or more embodiments, the compositionof the present invention is substantially alcohol-free, i.e., free ofshort chain alcohols. Short chain alcohols, having up to 5 carbon atomsin their carbon chain skeleton and one hydroxyl group, such as ethanol,propanol, isopropanol, butanol, iso-butanol, t-butanol and pentanol, areconsidered less desirable polar solvents due to their skin-irritatingeffect.

Thus, in certain embodiments, the composition is substantiallyalcohol-free and includes less than about 5% final concentration oflower alcohols, preferably less than about 2%, more preferably less thanabout 1%. However, in other embodiments, a short chain alcohol can beincluded in the composition, as long as the ratio between the shortchain alcohol and the polyol is less than 1:4 by weight.

Polymeric Agent

The composition of the present invention contains a polymeric agent. Ithas been documented that the presence of a polymeric agent is necessaryfor the creation of foam, having fine bubble structure, which does notreadily collapse upon release from the pressurized aerosol can. Thepolymeric agent serves to stabilize the foam composition and to controldrug residence in the target organ. Preferably, the polymeric agent issoluble or readily dispersible in the polyol; or in the mixture of apolyol and an additional polar solvent.

Non-limiting examples of polymeric agents that are soluble or readilydispersible in propylene glycol are Hydroxypropylcellulose and carbomer(homopolymer of acrylic acid is crosslinked with an allyl etherpentaerythritol, an allyl ether of sucrose, or an allyl ether ofpropylene, such as Carbopol® 934, Carbopol® 940, Carbopo® 941, Carbopol®980 and Carbopol® 981.

Other polymeric agents are suitable for use according to the presentinvention provided that they are soluble or readily dispersible in thepolyol; or in the mixture of a polyol and an additional polar solvent,on a case by case basis.

Exemplary polymeric agents include, in a non-limiting manner,naturally-occurring polymeric materials, such as locust bean gum, sodiumalginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum,sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guargum, cationic guars, hydroxypropyl guar gum, starch, amine-bearingpolymers such as chitosan; acidic polymers obtainable from naturalsources, such as alginic acid and hyaluronic acid; chemically modifiedstarches and the like, carboxyvinyl polymers, polyvinylpyrrolidone,polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acidpolymers, polyvinyl acetate polymers, polyvinyl chloride polymers,polyvinylidene chloride polymers and the like.

Additional exemplary polymeric agents include semi-synthetic polymericmaterials such as cellulose ethers, such as methylcellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxy propylmethyl cellulose, methylhydroxyethylcellulose,methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose,carboxymethyl cellulose, carboxymethylcellulosecarboxymethylhydroxyethylcellulose, and cationic celluloses.Polyethylene glycol, having molecular weight of 1000 or more (e.g., PEG1,000, PEG 4,000, PEG 6,000 and PEG 10,000) also have gelling capacityand while they are considered herein as “secondary polar solvents”, asdetailed herein, they are also considered polymeric agents.

Mixtures of the above polymeric agents are contemplated.

The concentration of the polymeric agent should be selected so that thecomposition, after filling into aerosol canisters, is flowable, and canbe shaken in the canister. In one or more embodiments, the concentrationof the polymeric agent is selected such that the viscosity of thecomposition, prior to filling of the composition into aerosol canisters,is less than 12,000 CPs, and more preferably, less than 10,000 CPs.

Surface-Active Agent

The composition of the present invention further contains asurface-active agent. Surface-active agents (also termed “surfactants”)include any agent linking oil and water in the composition, in the formof emulsion. A surfactant's hydrophilic/lipophilic balance (HLB)describes the emulsifier's affinity toward water or oil. HLB is definedfor non-ionic surfactants. The HLB scale ranges from 1 (totallylipophilic) to 20 (totally hydrophilic), with 10 representing an equalbalance of both characteristics. Lipophilic emulsifiers formwater-in-oil (w/o) emulsions; hydrophilic surfactants form oil-in-water(o/w) emulsions. The HLB of a blend of two emulsifiers equals the weightfraction of emulsifier A times its HLB value plus the weight fraction ofemulsifier B times its HLB value (weighted average).

According to one or more embodiments the composition contains a singlesurface active agent having an HLB value between about 7 and 12, or morethan one surface active agent and the weighted average of their HLBvalues is between about 7 and about 12.

Preferably, the composition of the present invention contains anon-ionic surfactant. Nonlimiting examples of possible non-ionicsurfactants include polysorbates, such as polyoxyethylene (20) sorbitanmonostearate (Tween 60) and poly(oxyethylene) (20) sorbitan monooleate(Tween 80); poly(oxyethylene) (POE) fatty acid esters, such as Myrj 45,Myrj 49, Myrj 52 and Myrj 59; poly(oxyethylene) alkylyl ethers, such aspoly(oxyethylene) cetyl ether, poly(oxyethylene) palmityl ether,polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether,brij 38, brij 52, brij 56 and brij W1; sucrose esters, partial esters ofsorbitol and its anhydrides, such as sorbitan monolaurate and sorbitanmonolaurate; mono or diglycerides, isoceteth-20, and mono-, di- andtri-esters of sucrose with fatty acids (sucrose esters).

Non-limiting examples of non-ionic surfactants that have HLB of about 7to about 12 include PEG 100 stearate (HLB=11), Laureth 4 (HLB=9.7) andcetomacrogol ether (e.g., polyethylene glycol 1000 monocetyl ether).

Yet, in additional embodiments, the composition contains a singlesurface active agent or a combination of surface active agents having anHLB values between about 9 and about 14; and in other embodiments, thecomposition contains one or more surface active agents, having an HLBvalue between about 2 and about 9.

In certain cases, the surface active agent is selected from the group ofcationic, zwitterionic, amphoteric and ampholytic surfactants, such assodium methyl cocoyl taurate, sodium methyl oleoyl taurate, sodiumlauryl sulfate, triethanolamine lauryl sulfate and betaines.

In one or more embodiments of the present invention, the surface-activeagent includes at least one non-ionic surfactant. Ionic surfactants areknown to be irritants. Therefore, non-ionic surfactants are preferred inapplications including sensitive tissue such as found in most mucosaltissues, especially when they are infected or inflamed. We havesurprisingly found that non-ionic surfactants alone provide foams ofexcellent quality, i.e. a score of “E” according to the grading scalediscussed herein below.

Thus, in a preferred embodiment, the surface active agent, thecomposition contains a non-ionic surfactant, or a mixture of non-ionicsurfactants as the sole surface active agent. Yet, in additionalembodiments, the foamable composition includes a mixture of at least onenon-ionic surfactant and at least one ionic surfactant in a ratio in therange of about 100:1 to 6:1. In further embodiments, surface activeagent comprises a combination of a non-ionic surfactant and an ionicsurfactant, at a ratio of between 1:1 and 20:1. The concentration of thesurface active agent is between about 0.1% and about 5%.

Hydrophobic Solvent

Optionally, the foamable carrier further contains at least onehydrophobic solvent. The identification of a “hydrophobic solvent”, asused herein, is not intended to characterize the solubilizationcapabilities of the solvent for any specific active agent or any othercomponent of the foamable composition. Rather, such information isprovided to aid in the identification of materials suitable for use as apart in the foamable compositions described herein.

A “hydrophobic solvent” as used herein refers to a material havingsolubility in distilled water at ambient temperature of less than about1 gm per 100 mL, more preferable less than about 0.5 gm per 100 mL, andmost preferably less than about 0.1 gm per 100 mL.

In one or more embodiments, the hydrophobic organic carrier is an oil,such as mineral oil, isopropyl palmitate, isopropyl isostearate,diisopropyl adipate, diisopropyl dimerate, maleated soybean oil, octylpalmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate,acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryloleate, tocopheryl linoleate, wheat germ glycerides, arachidylpropionate, myristyl lactate, decyl oleate, propylene glycolricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate,neopentylglycol dicaprylate/dicaprate, isononyl isononanoate,isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyldodecanol, unsaturated or polyunsaturated oils, such as olive oil, cornoil, soybean oil, canola oil, cottonseed oil, coconut oil, sesame oil,sunflower oil, borage seed oil, syzigium aromaticum oil, hempseed oil,herring oil, cod-liver oil, salmon oil, flaxseed oil, wheat germ oil,evening primrose oils; essential oils; and silicone oils, such asdimethicone, cyclomethicone, polyalkyl siloxanes, polyaryl siloxanes,polyalkylaryl siloxanes and polyether siloxane copolymers,polydimethylsiloxanes (dimethicones) andpoly(dimethylsiloxane)-(diphenyl-siloxane) copolymers.

Foam Adjuvant

Optionally, a foam adjuvant is included in the foamable carriers of thepresent invention to increase the foaming capacity of surfactants and/orto stabilize the foam. In one or more embodiments of the presentinvention, the foam adjuvant agent includes fatty alcohols having 15 ormore carbons in their carbon chain, such as cetyl alcohol and stearylalcohol (or mixtures thereof). Other examples of fatty alcohols arearachidyl alcohol (C20), behenyl alcohol (C22), 1-triacontanol (C30), aswell as alcohols with longer carbon chains (up to C50). Fatty alcohols,derived from beeswax and including a mixture of alcohols, a majority ofwhich has at least 20 carbon atoms in their carbon chain, are especiallywell suited as foam adjuvant agents. The amount of the fatty alcoholrequired to support the foam system is inversely related to the lengthof its carbon chains. Foam adjuvants, as defined herein are also usefulin facilitating improved spreadability and absorption of thecomposition.

In one or more embodiments of the present invention, the foam adjuvantagent includes fatty acids having 16 or more carbons in their carbonchain, such as hexadecanoic acid (C16) stearic acid (C18), arachidicacid (C20), behenic acid (C22), octacosanoic acid (C28), as well asfatty acids with longer carbon chains (up to C50), or mixtures thereof.As for fatty alcohols, the amount of fatty acids required to support thefoam system is inversely related to the length of its carbon chain.

Optionally, the carbon atom chain of the fatty alcohol or the fatty acidmay have at least one double bond. A further class of foam adjuvantagent includes a branched fatty alcohol or fatty acid. The carbon chainof the fatty acid or fatty alcohol also can be substituted with ahydroxyl group, such as 12-hydroxy stearic acid.

Additional Components

In an embodiment of the present invention, a composition of the presentinvention includes one or more additional components. Such additionalcomponents include but are not limited to anti perspirants, anti-staticagents, buffering agents, bulking agents, chelating agents, cleansers,colorants, conditioners, deodorants, diluents, dyes, emollients,fragrances, hair conditioners, humectants, pearlescent aids, perfumingagents, permeation enhancers, pH-adjusting agents, preservatives,protectants, skin penetration enhancers, softeners, solubilizers,sunscreens, sun blocking agents, sunless tanning agents, viscositymodifiers and vitamins. As is known to one skilled in the art, in someinstances a specific additional component may have more than oneactivity, function or effect.

In an embodiment of the present invention, the additional component is apH adjusting agent or a buffering agent. Suitable buffering agentsinclude but are not limited to acetic acid, adipic acid, calciumhydroxide, citric acid, glycine, hydrochloric acid, lactic acid,magnesium aluminometasilicates, phosphoric acid, sodium carbonate,sodium citrate, sodium hydroxide, sorbic acid, succinic acid, tartaricacid, and derivatives, salts and mixtures thereof.

In an embodiment of the present invention, the additional component isan emollient. Suitable emollients include but are not limited to mineraloil, lanolin oil, coconut oil, cocoa butter, olive oil, aloe veraextract, jojoba oil, castor oil, fatty acids, fatty alcohols,diisopropyl adipate, hydroxybenzoate esters, benzoic acid esters of C9to C15 alcohols, isononyl iso-nonanoate, silicone oils, polyethers, C12to C15 alkyl benzoates, oleic acid, stearic fatty acid, cetyl alcohols,hexadecyl alcohol, dimethyl polysiloxane, polyoxypropylene cetyl ether,polyoxypropylene butyl ether, and derivatives, esters, salts andmixtures thereof.

In an embodiment of the present invention, the additional component is ahumectant. Suitable humectants include but are not limited to guanidine,urea, glycolic acid, glycolate salts, ammonium glycolate, quaternaryalkyl ammonium glycolate, lactic acid, lactate salts, ammonium lactate,quaternary alkyl ammonium lactate, aloe vera, aloe vera gel, allantoin,urazole, alkoxylated glucose, hyaluronic acid, lactamidemonoethanolamine, acetamide monoethanolamine and derivatives, esters,salts and mixtures thereof.

In an embodiment of the present invention, the additional component is apreservative. Suitable preservatives include but are not limited to C12to C15 alkyl benzoates, alkyl p-hydroxybenzoates, aloe vera extract,ascorbic acid, benzalkonium chloride, benzoic acid, benzoic acid estersof C9 to C15 alcohols, butylated hydroxytoluene, castor oil, cetylalcohols, chlorocresol, citric acid, cocoa butter, coconut oil,diazolidinyl urea, diisopropyl adipate, dimethyl polysiloxane, DMDMhydantoin, ethanol, fatty acids, fatty alcohols, hexadecyl alcohol,hydroxybenzoate esters, iodopropynyl butylcarbamate, isononyliso-nonanoate, jojoba oil, lanolin oil, methylparaben, mineral oil,oleic acid, olive oil, polyethers, polyoxypropylene butyl ether,polyoxypropylene cetyl ether, potassium sorbate, silicone oils, sodiumpropionate, sodium benzoate, sodium bisulfite, sorbic acid, stearicfatty acid, vitamin E, vitamin E acetate and derivatives, esters, saltsand mixtures thereof.

In an embodiment of the present invention, the additional component is askin penetration enhancer. Suitable skin penetration enhancers includebut are not limited to acetone, acyl lactylates, acyl peptides,acylsarcosinates, alkanolamine salts of fatty acids, alkyl benzenesulphonates, alkyl ether sulphates, alkyl sulphates, anionicsurface-active agents, benzyl benzoate, benzyl salicylate,butan-1,4-diol, butyl benzoate, butyl laurate, butyl myristate, butylstearate, cationic surface-active agents, citric acid,cocoamidopropylbetaine, decyl methyl sulfoxide, decyl oleate, dibutylazelate, dibutyl phthalate, dibenzyl sebacate, dibutyl sebacate, dibutylsuberate, dibutyl succinate, dicapryl adipate, didecyl phthalate,diethylene glycol, diethyl sebacate, diethyl-m-toluamide,di(2-hydroxypropyl) ether, diisopropyl adipate, diisopropyl sebacate,N,N-dimethyl acetamide, dimethyl azelate, N,N-dimethyl formamide,1,5-dimethyl-2-pyrrolidone, dimethyl sebacate, dimethyl sulphoxide,dioctyl adipate, dioctyl azelate, dioctyl sebacate, 1,4 dioxane,1-dodecylazacyloheptan-2-one, dodecyl dimethyl amine oxides, ethylcaprate, ethyl caproate, ethyl caprylate, 2-ethyl-hexyl pelargonate,ethyl-2-hydroxypropanoate, ethyl laurate, ethyl myristate,1-ethyl-2-pyrrolidone, ethyl salicylate, hexyl laurate,2-hydroxyoctanoic acid, 2-hydroxypropanoic acid, 2-hydroxypropionicacid, isethionates, isopropyl isostearate, isopropyl palmitate, guarhydroxypropyltrimonium chloride, hexan-2,5-diol, khellin, lamepons,lauryl alcohol, maypons, metal salts of fatty acids, methyl nicotinate,2-methyl propan-2-ol, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,methyl taurides, miranol, nonionic surface-active agents, octyl alcohol,octylphenoxy polyethoxyethanol, oleic ethanolamide, pleyl alcohol,pentan-2,4-diol, phenoxyethanol, phosphatidyl choline, phosphine oxides,polyalkoxylated ether glycollates, poly(diallylpiperidinium chloride),poly(dipropyldiallylammonium chloride), polyglycerol esters,polyoxyethylene lauryl ether, polyoxy:polyoxyethylene stearate,polyoxypropylene 15 stearyl ether, poly(vinyl pyridinium chloride),propan-1-ol, propan-2-ol, propylene glycol dipelargonate, pyroglutamicacids, 2-pyrrolidone, pyruvic acids, Quaternium 5, Quaternium 18,Quaternium 19, Quaternium 23, Quaternium 31, Quaternium 40, Quaternium57, quartenary amine salts, quaternised poly(dimethylaminoethylmethacryl-ate), quaternised poly (vinyl alcohol),sapamin hydrochloride, sodium cocaminopropionate, sodium dioctylsulphonsuccinate, sodium laurate, sodium lauryl ether sulphate, sodiumlauryl sulphate, sugar esters, sulphosuccinate, tetrahydrofuran,tetrahydrofurfural alcohol, transcutol, triethanolamine dodecyl benzenesulphonate, triethanolamine oleate, urea, water and derivatives, esters,salts and mixtures thereof.

Propellants

Examples of suitable propellants include volatile hydrocarbons such asbutane, propane, isobutane and fluorocarbon gases, or mixtures thereof.

In certain embodiments, fluorohydrocarbon propellants, other thanchloro-fluoro carbons (CMCs) which are non-ozone-depleting propellants,are particularly useful in the production of a non-flammable foamablecomposition.

Such propellants include, but are not limited to hydrofluorocarbon (HFC)propellants, that contain no chlorine atoms, and as such, fallscompletely outside concerns about stratospheric ozone destruction bychlorofluorocarbons or other chlorinated hydrocarbons. Exemplarynon-flammable propellants according to this aspect of the inventioninclude propellants made by DuPont under the registered trademark Dymel,such as 1,1,1,2 tetrafluorethane (Dymel 134), and 1,1,1,2,3,3,3heptafluoropropane (Dymel 227), 1,1, difluoro ethane (Dymel 152) and1,1,1,3,3,3 hexafluoropropane. HFCs possess Ozone Depletion Potential of0.00 and thus, they are allowed for use as propellant in aerosolproducts.

The propellant makes up about 5-25 wt % of the foamable composition.Aerosol propellants are used to generate and administer the foamablecomposition as a foam. The total composition including propellant,foamable compositions and optional ingredients is referred to as thefoamable composition.

Hygroscopic Property of the Composition

A hydroscopic substance is a substance that absorbs water readily fromits surroundings. Microorganisms require water to grow and reproduce,and such water requirements are best defined in terms of water activityof the substrate. The water activity of a solution is expressed asAw=P/Po, where P is the water vapor pressure of the solution and Po isthe vapor pressure of pure water at the same temperature. Addition of ahygroscopic substance to an aqueous solution in which a microorganism isgrowing will have the effect of lowering the Aw, with a consequenteffect upon cell growth. Every microorganism has a limiting Aw, belowwhich it will not grow, e.g., for streptococci, klebsiella spp.,escherichia coli, clostridium perfringens, and pseudomonas spp. the Awvalue is 0.95. Staphylococcus aureus is most resistant and canproliferate with an Aw as low as 0.86.

The water activity of a product can be determined from the relativehumidity of the air surrounding the sample when the air and the sampleare at equilibrium. Measurement is performed by placing a sample in anenclosed space where this equilibrium can take place. Once this occurs,the water activity of the sample and the relative humidity of the airare equal. The measurement taken at equilibrium is called an equilibriumrelative humidity or ERH. The relationship between the water activityand ERH is in accordance with the following formula: Aw=ERH/100

Various types of water activity instruments are commercially available.One exemplary instrument uses chilled-mirror dewpoint technology whileother instruments measure relative humidity with sensors that changeelectrical resistance or capacitance.

Polyols, PEGs and other polar solvents have a great affinity for water,and as such, they exhibit hygroscopic properties. The concentration ofthe polyol, the PEG and/or other polar solvents determines the Aw of thecarrier. In one or more embodiments, the polyols, the PEG and/or thesecondary polar solvent is contained in the composition of the presentinvention at a sufficient concentration to provide an Aw value of thehygroscopic carrier of less than 0.9. In other embodiments, theconcentration of the polyol, the PEG and/or secondary polar solvent inthe composition is selected to provide a Aw value selected from theranges of (1) about 0.8 and about 0.9; (2) about 0.7 and about 0.8; and(3) less than about 0.7.

As such, a composition containing a polyol, a PEG with or without asecondary polar solvent can be used as topical treatment of superficialinfectious conditions.

The advantage of providing a hygroscopic composition in a pressurizedpackaging presentation is readily perceived. The usage of all otherpresentations, such as solutions, creams, lotions, ointments and thelike involves repeated opening of the package closure, resulting inabsorption of water from the surrounding environment and a subsequentelevation of the Aw (thus lowering the hygroscopicity of the product,and therefore decreasing its anti-infective potential. By contrast, apressurized packaging does not allow for any humidity to be absorbed bythe preparation, and therefore, the hygroscopic character of thecomposition cannot be damaged.

In one or more embodiments, the hygroscopic composition of the presentinvention further contains an anti-infective agent, selected from thegroup of an antibiotic agent, an antibacterial agent, an antifungalagent, an agent that controls yeast, an antiviral agent and anantiparasitic agent. Combining the anti-infective effect of ahygroscopic composition, which acts through a dehydration mechanism,with an additional anti-infective agent that acts through alternatemechanisms results in a synergistic effect and consequently highersuccess rate of the treatment.

Composition and Foam Physical Characteristics and Advantages

A pharmaceutical or cosmetic composition manufactured using the foamablecarrier of the present invention is very easy to use. When applied ontothe afflicted body surface of mammals, i.e., humans or animals, it is ina foam state, allowing free application without spillage. Upon furtherapplication of a mechanical force, e.g., by rubbing the composition ontothe body surface, it freely spreads on the surface and is rapidlyabsorbed.

The foamable composition of the present invention is stable, having anacceptable shelf-life of at least one year, or preferably, at least twoyears at ambient temperature, as revealed in accelerated stabilitytests. Organic carriers and propellants tend to impair the stability ofemulsions and to interfere with the formation of stable foam uponrelease from a pressurized container. It has been observed, however,that the foamable compositions according to the present invention aresurprisingly stable. Following accelerated stability studies, theydemonstrate desirable texture; they form fine bubble structures that donot break immediately upon contact with a surface, spread easily on thetreated area and absorb quickly.

The composition should also be free flowing, to allow it to flow throughthe aperture of the container, e.g., and aerosol container, and createan acceptable foam.

Foam quality can be graded as follows:

Grade E (excellent): very rich and creamy in appearance, does not showany bubble structure or shows a very fine (small) bubble structure; doesnot rapidly become dull; upon spreading on the skin, the foam retainsthe creaminess property and does not appear watery.

Grade G (good): rich and creamy in appearance, very small bubble size,“dulls” more rapidly than an excellent foam, retains creaminess uponspreading on the skin, and does not become watery.

Grade FG (fairly good): a moderate amount of creaminess noticeable,bubble structure is noticeable; upon spreading on the skin the productdulls rapidly and becomes somewhat lower in apparent viscosity.

Grade F (fair): very little creaminess noticeable, larger bubblestructure than a “fairly good” foam, upon spreading on the skin itbecomes thin in appearance and watery.

Grade P (poor): no creaminess noticeable, large bubble structure, andwhen spread on the skin it becomes very thin and watery in appearance.

Grade VP (very poor): dry foam, large very dull bubbles, difficult tospread on the skin.

Topically administrable foams are typically of quality grade E or G,when released from the aerosol container. Smaller bubbles are indicativeof more stable foam, which does not collapse spontaneously immediatelyupon discharge from the container. The finer foam structure looks andfeels smoother, thus increasing its usability and appeal.

As further aspect of the foam is breakability. The breakable foam isthermally stable, yet breaks under sheer force. Sheer-force breakabilityof the foam is clearly advantageous over thermally induced breakability.Thermally sensitive foams immediately collapse upon exposure to skintemperature and, therefore, cannot be applied on the hand and afterwardsdelivered to the afflicted area.

The foam of the present invention has several advantages, when comparedwith hydroalcoholic foam compositions, such as described in WO2004/071479:

-   (1) Breakability. The foam of the present invention is thermally    stable. Unlike hydroalcoholic foam compositions of the prior art,    the foam of the present invention is not “quick breaking”, i.e., it    does not readily collapse upon exposure to body temperature    environment. Sheer-force breakability of the foam is clearly    advantageous over thermally induced breakability, since it allows    comfortable application and well directed administration to the    target area.-   (2) Skin drying and skin barrier function. Short chain alcohols are    known to dry the skin and impair the integrity of the skin barrier.    By contrast, including a film forming agent in the composition of    the present invention foes not cause unwanted skin barrier damage.-   (3) Irritability. Due to the lack of alcohol and improvement in skin    barrier function, skin irritability is eliminated.

Another property of the foam is specific gravity, as measured uponrelease from the aerosol can. Typically, foams have specific gravity ofless than 0.12 g/mL; or less than 0.10 g/mL; or less than 0.08 g/mL,depending on their composition and on the propellant concentration.

Pharmaceutical Composition

The foamable composition of the present invention is an ideal vehiclefor active pharmaceutical ingredients and active cosmetic ingredients.In the context of the present invention, active pharmaceuticalingredients and active cosmetic ingredients are collectively termed“active agent” or “active agents”. A foamable composition, comprising anactive agent has the following advantages:

-   -   1. The foamable composition provides a preferred solvent for        active agents, particularly water-insoluble agents.    -   2. The inclusion of a polyol and/or a PEG and a secondary polar        solvent in the foamable composition facilitates a co-solvent        effect, resulting increased concentrations of soluble active        agent in the dosage form, thus facilitating enhanced skin        penetration of the active agent. In many cases, increased        penetration is positively correlated with improved clinical        outcome. In certain case, attaining an increased drug        penetration into the target site of action enables a decrease of        treatment frequency, for example, from twice or three times        daily to once daily.    -   3. Polyols and PEGs; and combinations of a polyol and/or PEG        with a secondary polar solvent are known as skin penetration        enhancers, thus, increasing drug residence in the target area        and increasing clinical efficacy, as detailed above.    -   4. The fact that the composition contains no water, or up to 25%        and more preferably up to 10% water minimizes the probability of        degradation of water-sensitive active agents. Furthermore, as        exemplified herein, a foam containing a polyol and/or PEG with        no water at all can be formed in accordance with the composition        and process of the present invention. Such compositions ensure        high stability of water sensitive active agents.    -   5. Combining the anti-infective effect of a hygroscopic        composition, which acts through a dehydration mechanism, with an        additional anti-infective agent, selected from the group of an        antibiotic agent, an antibacterial agent, an antifungal agent,        an agent that controls yeast, an antiviral agent and an        antiparasitic agent, that acts through alternate mechanisms        results in a synergistic effect and consequently higher success        rate of the treatment.    -   6. The foamable polyol composition in contained in an        impermeable pressurized packaging presentation is impermeable        and thus, the active agent is not exposed to environmental        degradation factors, such as light and oxidating agent during        storage.

Thus, in a preferred embodiment of the present invention, thecomposition includes at least one active agent.

-   -   a. a therapeutically effective concentration of an active agent;        and    -   b. about 50% to about 98% of a polar solvent, selected from the        group consisting of a polyol and a polyethylene glycol;    -   c. 0% to about 48% of a secondary polar solvent;    -   d. about 0.2% to about 5% by weight of a surface-active agent;    -   e. about 0.01% to about 5% by weight of at least one polymeric        agent; and    -   f. a liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition.

In the context of combining a hygroscopic carrier according to thepresent invention and an anti-infective active agent, a pharmaceuticalcomposition is provided, including:

-   -   a. a hygroscopic substance at a sufficient concentration to        provide an Aw value of the hygroscopic carrier of less than 0.9.        The concentration of the hygroscopic substance in the        composition can be designed to provide a Aw value selected from        the ranges of (1) about 0.8 and about 0.9; (2) about 0.7 and        about 0.8; and (3) less than about 0.7;    -   b. about 0.2% to about 5% by weight of a surface-active agent;    -   c. about 0.01% to about 5% by weight of at least one polymeric        agent selected from a bioadhesive agent, a gelling agent, a film        forming agent and a phase change agent;    -   d. a therapeutically effective concentration of an        anti-infective agent; and    -   e. a liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition.

An exemplary case for the inclusion of an anti-infective agent in ahygroscopic composition is provided herewith. It has been surprisinglydiscovered that combining an antifungal agent in a hygroscopiccomposition results in an anti-infective effect on strains that are notsupposed to be affected by the said antifungal agent. For example,terbinafine is know to be highly effective against dermatophitepathogens, but not against candida. In-vitro studies have revealed,however that terbinafine, dissolved in a hygroscopic carrier,effectively inhibited the spreading of candida albicans, while a controlpreparation, comprising the same concentration of terbinafine in anemulsion base was not effective. Thus, combining an antifungal agent ina hygroscopic composition results in an expansion of the spectrum ofinfective strains that can benefit form the therapy, and furthermore, incan render an improved effect of such a composition on mixed infectionsor in infections that are not accurately diagnosed.

Consequently, in another aspect of the present invention, apharmaceutical composition, which possesses an improved antifungalactivity or that possesses an antifungal activity on an expandedspectrum of pathogens, is provided, including:

-   -   a. a hygroscopic composition, comprising a hygroscopic substance        at a sufficient concentration to provide an Aw value of the        hygroscopic carrier of less than 0.9. The concentration of the        hygroscopic substance in the composition can be designed to        provide a Aw value selected from the ranges of (1) about 0.8 and        about 0.9; (2) about 0.7 and about 0.8; and (3) less than about        0.7;    -   b. an anti-infective agent, selected from the group of an        antibiotic agent, an antibacterial agent, an antifungal agent,        an agent that controls yeast, an antiviral agent and an        antiparasitic agent. Preferably, the anti-infective agent is an        antifungal agent, and more preferably the anti-infective agent        is terbinafine.

Active Agents

Suitable active agents include but are not limited to active herbalextracts, acaricides, age spot and keratose removing agents, allergen,analgesics, local anesthetics, antiacne agents, antiallergic agents,antiaging agents, antibacterials, antibiotics, antiburn agents,anticancer agents, antidandruff agents, antidepressants, antidermatitisagents, antiedemics, antihistamines, antihelminths, antihyperkeratolyteagents, antiinflammatory agents, antiirritants, antilipemics,antimicrobials, antimycotics, antiproliferative agents, antioxidants,anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosaceaagents antiseborrheic agents, antiseptic, antiswelling agents, antiviralagents, antiyeast agents, astringents, topical cardiovascular agents,chemotherapeutic agents, corticosteroids, dicarboxylic acids,disinfectants, fungicides, hair growth regulators, hormones, hydroxyacids, immunosuppressants, immunoregulating agents, insecticides, insectrepellents, keratolytic agents, lactams, metals, metal oxides,mitocides, neuropeptides, non-steroidal anti-inflammatory agents,oxidizing agents, pediculicides, photodynamic therapy agents, retinoids,sanatives, scabicides, self tanning agents, skin whitening agents,asoconstrictors, vasodilators, vitamins, vitamin D derivatives, woundhealing agents and wart removers. As is known to one skilled in the art,in some instances a specific active active agent may have more than oneactivity, function or effect.

In an embodiment of the present invention, the active agent is an activeherbal extract. Suitable active herbal extracts include but are notlimited to angelica, anise oil, astragali radix, azalea, benzyl acetate,birch tar oil, bomyl acetate, cacumen biotae, camphor, cantharidin,capsicum, cineole, cinnamon bark, cinnamon leaf, citronella,citroneliol, citronellyl acetate, citronellyl formate, eucalyptus,eugenyl acetate, flos carthami, fructus mori, garlic, geraniol,geranium, geranyl acetate, habanera, isobutyl angelicate, lavender,ledum latifolium, ledum palustre, lemongrass, limonene, linalool,linalyl acetate, methyl anthranilate, methyl cinnamate, mezereum, neem,nerol, neryl acetate, nettle root extract, oleum ricini, oregano,pinenes, .alpha.-pinene, .beta.-pinene, radix angelicae sinesis, radixpaenoiae rubra, radix polygoni multiflori, radix rehmanniae, rhizomapinelliae, rhizoma zingiberis recens, sabadilla, sage, sandalwood oil,saw palmetto extract, semen sesami nignrum, staphysagria, tea tree oil,terpene alcohols, terpene hydrocarbons, terpene esters, terpinene,terpineol, terpinyl acetate and derivatives, esters, salts and mixturesthereof. In an embodiment of the present invention, the active agent isan acaricide. Suitable acaricides include but are not limited toamitraz, flumethrin, fluvalinate and derivatives, esters, salts andmixtures thereof.

In an embodiment of the present invention, the active agent is an agespot and keratoses removing agent. Suitable age spot and keratosesremoving agent include but are not limited to hydroxy acids, azelaicacid and other related dicarboxylic acids, retinoids, kojic acid,arbutin, nicotinic, ascorbic acid, hydroquinone and derivatives, esters,salts and mixtures thereof. Certain nonsteroidal anti-inflammatoryagents, such as diclofenac are also useful for the treatment ofkeratoses.

In an embodiment of the present invention, the active agent is ananalgesic. Suitable analgesics include but are not limited tobenzocaine, butamben picrate, dibucaine, dimethisoquin, dyclonine,lidocaine, pramoxine, tetracaine, salicylates and derivatives, esters,salts and mixtures thereof.

In an embodiment of the present invention, the active agent is a localanesthetic. Suitable local anesthetics include but are not limited tobenzocaine, benzyl alcohol, bupivacaine, butamben picrate,chlorprocaine, cocaine, dibucaine, dimethisoquin, dyclonine, etidocaine,hexylcaine, ketamine, lidocaine, mepivacaine, phenol, pramoxine,procaine, tetracaine, salicylates and derivatives, esters, salts andmixtures thereof.

In an embodiment of the present invention, the active agent is anantiacne agent. Suitable antiacne agents include but are not limited toN-acetylcysteine, adapalene, azelaic acid, benzoyl peroxide, cholate,clindamycin, deoxycholate, erythromycin, flavinoids, glycolic acid,meclocycline, metronidazol, mupirocin, octopirox, phenoxy ethanol,phenoxy proponol, pyruvic acid, resorcinol, retinoic acid, salicylicacid, scymnol sulfate, sulfacetamide-sulfur, sulfur, tazarotene,tetracycline, tretinoin triclosan and derivatives, esters, salts andmixtures thereof.

In an embodiment of the present invention, the active agent is anantiaging agent. Suitable antiaging agents include but are not limitedto sulfur-containing D and L amino acids, alpha-hydroxy acids s,beta-hydroxy acids (e.g. salicylic acid), urea, hyaluronic acid, phyticacid, lipoic acid; lysophosphatidic acid, skin peel agents (e.g.,phenol, resorcinol and the like), vitamin B3 compounds (e.g.,niacinamide, nicotinic acid and nicotinic acid salts and esters,including non-vasodilating esters of nicotinic acid (such as tocopherylnicotinate), nicotinyl amino acids, nicotinyl alcohol esters ofcarboxylic acids, nicotinic acid N-oxide and niacinamide N-oxide),vitamin B5 and retinoids (e.g., retinol, retinal, retinoic acid, retinylacetate, retinyl palmitate, retinyl ascorbate) skin barrier formingagents, melatonin and derivatives, esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is anantibiotic. The terms “antibiotic” as used herein shall include, but isnot limited to, any substance being destructive to or inhibiting thegrowth of bacteria or any substance having the capacity to inhibit thegrowth of or to destroy bacteria. In one or more embodiments, theantibiotic agent is selected from the group consisting of a beta-lactamantibiotic, an aminoglycoside, an ansa-type antibiotic, ananthraquinone, an azole, an antibiotic glycopeptide, a macrolide, anantibiotic nucleoside, an antibiotic peptide, an antibiotic polyene, anantibiotic polyether, an antibiotic quinolone, an antibiotic steroid, asulfonamide, an antibiotic metal, an oxidizing agent, a periodate, ahypochlorite, a permanganate, a substance that release free radicalsand/or active oxygen, a cationic antimicrobial agent, a quaternaryammonium compound, a biguanide, a triguanide, a bisbiguanide, apolymeric biguanide, and analogs, derivatives, salts, ions and complexesthereof.

Suitable antibiotics include but are not limited to amanfadinehydrochloride, amanfadine sulfate, amikacin, arnikacin sulfate,aminoglycosides, amoxicillin, ampicillin, ansamycins, bacitracin,beta-lactams, candicidin, capreomycin, carbenicillin, cephalexin,cephaloridine, cephalothin, cefazolin, cephapirin, cephradine,cephaloglycin, chloramphenicols, chlorhexidine, chlorhexidine gluconate,chlorhexidine hydrochloride, chloroxine, chlorquinaldol,chlortetracycline, chlortetracycline hydrochloride, ciprofloxacin,circulin, clindamycin, clindamycin hydrochloride, clotrimazole,cloxacillin, demeclocycline, diclosxacillin, diiodohydroxyquin,doxycycline, ethambutol, ethambutol hydrochloride, erythromycin,erythromycin estolate, erythromycin stearate, farnesol, floxacillin,gentamicin, gentamicin sulfate, gramicidin, griseofulvin, haloprogin,haloquinol, hexachlorophene, iminocyldline, iodate, iodine,iodochlorhydroxyquin, kanamycin, kanamycin sulfate, lincomycin,lineomycin, lineomycin hydrochloride, macrolides, meclocycline,methacycline, methacycline hydrochloride, methenamine, methenaminehippurate, methenamine mandelate, methicillin, metronidazole,miconazole, miconazole hydrochloride, microcrystalline andnanocrystalline particles of silver, copper, zinc, mercury, tin, lead,bismuth, cadmium and chromium, minocycline, minocycline hydrochloride,mupirocin, nafcillin, neomycin, neomycin sulfate, netilmicin, netilmicinsulfate, nitrofurazone, norfloxacin, nystatin, octopirox, oleandomycin,orcephalosporins, oxacillin, oxytetracycline, oxytetracyclinehydrochloride, parachlorometa xylenol, paromomycin, paromomycin sulfate,penicillins, penicillin G, penicillin V, pentamidine, pentamidinehydrochloride, phenethicillin, polymyxins, quinolones, streptomycinsulfate, tetracycline, tobramycin, tolnaftate, triclosan, trifampin,rifamycin, rolitetracycline, spectinomycin, spiramycin, streptomycin,sulfonamide, tetracyclines, tetracycline, tobramycin, tobramycinsulfate, triclocarbon, triclosan, trimethoprim-sulfamethoxazole,tylosin, vancomycin, yrothricin and derivatives, esters, salts andmixtures thereof.

In an embodiment of the present invention, the active agent is anantidandruff agent. Suitable antidandruffagents include but are notlimited to aminexil, benzalkonium chloride, benzethonium chloride,3-bromo-1-chloro-5,5-dimethyl-hydantoin, chloramine B, chloramine T,chlorhexidine, N-chlorosuccinimide,climbazole-,1,3-dibromo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethyl-hydantoin,betulinic acid, betulonic acid, celastrol, crataegolic acid, cromakalin,cyproterone acetate, dutasteride, finesteride, ibuprofen, ketoconozole,oleanolic acid, phenytoin, picrotone olamine, salicylic acid, seleniumsulphides, triclosan, triiodothyronine, ursolic acid, zinc gluconate,zinc omadine, zinc pyrithione and derivatives, esters, salts andmixtures thereof.

In an embodiment of the present invention, the active agent is anantihistamine. Suitable antihistamines include but are not limited tochlorcyclizine, diphenhydramine, mepyramine, methapyrilene,tripelennamine and derivatives, esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is anantimycotic Also termed antifungal agent. The terms “antimycotic” and“antifungal” as used herein include, but is not limited to, anysubstance being destructive to or inhibiting the growth of fungi andyeast or any substance having the capacity to inhibit the growth of orto destroy fungi and/or yeast.

In one or more embodiments, the antifungal agent is an agent that isuseful in the treatment of a superficial fungal infection of the skin,dermatophytosis, microsporum, trichophyton and epidermophytoninfections, candidiasis, oral candidiasis (thrush), candidiasis of theskin and genital mucous membrane, candida paronychia, which inflicts thenail and nail bed and genital and vaginal candida, which inflictgenitalia and the vagina.

Suitable antimycotics include but are not limited to allylamines,amorolfine, amphotericin B, azole compounds, bifonazole, butoconazole,chloroxine, clotrimazole, ciclopirox olamine, clotrimazole, econazole,elubiol, fenticonazole, fluconazole, flucytosine (5FC), griseofulvin,itraconazole, ketoconazole, mafenide acetate, miconazole, naftifine,natamycin, tolnaftate, nystatin, polyenes, oxiconazole, sulbentine,sulconazole, terbinafine, terconazole, tioconazole, undecylenic acid andderivatives, esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is anantipruritic. Suitable antipruritics include but are not limited tomenthol, methdilazine, trimeprazine, urea and derivatives, esters, saltsand mixtures thereof.

In an embodiment of the present invention, the active agent is anadditional antipsoriatic agent. Suitable additional antipsoriatic agentsinclude but are not limited to 6-aminonicotinamide, 6-aminonicotinicacid, 2-aminopyrazinamide, anthralin, 6-carbamoylnicotinamide,6-chloronicotinamide, 2-carbamoylpyrazinamide, corticosteroids,6-dimethylaminonicotinamide, dithranol, 6-formylaminonicotinamide,6-hydroxy nicotinic acid, 6-substituted nicotinamides, 6-substitutednicotinic acid, 2-substituted pyrazinamide, tazarotene,thionicotinamide, trichothecene mycotoxins and derivatives, esters,salts and mixtures thereof.

In an embodiment of the present invention, the active agent is anantirosacca agent. Suitable antirosacea agents include but are notlimited to azelaic acid, metronidazole, sulfacetamide and derivatives,esters, salts and mixtures thereof. Certain nonsteroidalanti-inflammatory agents, such as salicylic acid, salycilates, piroxicamand diclofenac are also useful for the treatment of Rosacea.

In an embodiment of the present invention, the active agent is anantiseborrheic agent. Suitable antiseborrheic agents include but are notlimited to glycolic acid, salicylic acid, selenium sulfide, zincpyrithione, a dicarboxylic acid, such as azelaic acid and derivatives,esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is anantiviral agent. Suitable antiviral agents include but are not limitedto acyclovir, gancyclovir, ribavirin, amantadine, rimantadinenucleoside-analog reverse transcriptase inhibitors, such as zidovudine,didanosine, zalcitabine, tavudine, lamivudine and vidarabine,non-nucleoside reverse transcriptase inhibitors, such as nevirapine anddelavirdine, protease inhibitors, such as saquinavir, ritonavir,indinavir and nelfinavir, and interferons and derivatives, esters, saltsand mixtures thereof.

In an embodiment of the present invention, the active agent is achemotherapeutic agent. Suitable chemotherapeutic agents include but arenot limited to daunorubicin, doxorubicin, idarubicin, amrubicin,pirarubicin, epirubicin, mitoxantrone, etoposide, teniposide,vinblastine, vincristine, mitomycin C, 5-FU, paclitaxel, docetaxel,actinomycin D, colchicine, topotecan, irinotecan, gemcitabinecyclosporin, verapamil, valspodor, probenecid, MK571, GF120918,LY335979, biricodar, terfenadine, quinidine, pervilleine A, XR9576 andderivatives, esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is acorticosteroid. Suitable corticosteroids include but are not limited toalclometasone dipropionate, amcinafel, amcinafide, amcinonide,beclomethasone, beclomethasone dipropionate, betamethsone, betamethasonebenzoate, betamethasone dexamethasone-phosphate, dipropionate,betamethasone valerate, budesonide, chloroprednisone, chlorprednisoneacetate, clescinolone, clobetasol, clobetasol propionate, clobetasolvalerate, clobetasone, clobetasone butyrate, clocortelone, cortisone,cortodoxone, craposone butyrate, desonide, desoxymethasone,dexamethasone, desoxycorticosterone acetate, dichlorisone, diflorasonediacetate, diflucortolone valerate, diflurosone diacetate,diflurprednate, fluadrenolone, flucetonide, flucloronide, flucloroloneacetonide, flucortine butylesters, fludroxycortide, fludrocortisone,flumethasone, flumethasone pivalate, flumethasone pivalate, flunisolide,fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl,fluocortolone, fluorometholone, fluosinolone acetonide, fluperolone,fluprednidene acetate, fluprednisolone hydrocortamate, fluradrenolone,fluradrenolone acetonide, flurandrenolone, fluticasone, halcinonide,halobetasol, hydrocortisone, hydrocortisone acetate, hydrocortisonebutyrate, hydrocortisone cyclopentylpropionate, hydrocortisone valerate,hydroxyltriamcinolone, medrysone, meprednisone, .alpha.-methyldexamethasone, methylprednisolone, methylprednisolone acetate,mometasone furoate, paramethasone, prednisolone, prednisone,pregnenolone, progesterone, spironolactone, triamcinolone, triamcinoloneacetonide and derivatives, esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is a hairgrowth regulator. Suitable hair growth regulators include but are notlimited to N-acetylgalactosamine, N-acetylglucosamine,N-acetylmannosamine, acitretin, aminexil, ascomycin, asiatic acid,azelaic acid, benzalkonium chloride, benzethonium chloride, benzydamine,benzyl nicotinate, benzoyl peroxide, benzyl peroxide, betulinic acid,betulonic acid, calcium pantothenate, celastrol, cepharanthine,chlorpheniramine maleate, clinacycin hydrochloride, crataegolic acid,cromakalin, cyproterone acetate, diazoxide, diphenhydraminehydrochloride, dutasteride, estradiol, ethyl-2-hydroxypropanoate,finasteride, D-fucono-1,5-lactone,furoate, L-galactono-1,4-lactone,D-galactosamine, D-glucaro-1,4-lactone, D-glucosamine-3-sulphatc,hinokitiol, hydrocortisone, 2-hydroxypropionic acid, isotretinoin,itraconazole, ketoconazole, latanoprost, 2-methyl propan-2-ol,minocyclin, minoxidil, mipirocin, mometasone, oleanolic acid, panthenol,1,10-phenanthroline, phenytoin, prednisolone, progesterone, propan-2-ol,pseudoterins, resorcinol, selenium sulfide, tazarotene, triclocarbon,triclosan, triiodothyronine, ursolic acid, zinc pyrithione andderivatives, esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is ahormone. Suitable hormones include but are not limited tomethyltestosterone, androsterone, androsterone acetate, androsteronepropionate, androsterone benzoate, androsteronediol,androsteronediol-3-acetate, androsteronediol-17-acetate,androsteronediol 3-17-diacetate, androsteronediol-17-benzoate,androsteronedione, androstenedione, androstenediol,dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate,dromostanolone, dromostanolone propionate, ethylestrenol,fluoxymesterone, nandrolone phenpropionate, nandrolone decanoate,nandrolone furylpropionate, nandrolone cyclohexane-propionate,nandrolone benzoate, nandrolone cyclohexanecarboxylate,androsteronediol-3-acetate-1-7-benzoate, oxandrolone, oxymetholone,stanozolol, testosterone, testosterone decanoate, 4-dihydrotestosterone,5a-dihydrotestosterone, testolactone, 17a-methyl-19-nortestosterone,desogestrel, dydrogesterone, ethynodiol diacetate, medroxyprogesterone,levonorgestrel, medroxyprogesterone acetate, hydroxyprogesteronecaproate, norethindrone, norethindrone acetate, norethynodrel,allylestrenol, 19-nortestosterone, lynoestrenol, quingestanol acetate,medrogestone, norgestrienone, dimethisterone, ethisterone, cyproteroneacetate, chlormadinone acetate, megestrol acetate, norgestimate,norgestrel, desogrestrel, trimegestone, gestodene, nomegestrol acetate,progesterone, 5a-pregnan-3b,20a-diol sulfate, 5a-pregnan-3b,20b-diolsulfate, 5a-pregnan-3b-ol-20-one, 16,5a-pregnen-3b-ol-20-one,4-pregnen-20b-ol-3-one-20-sulfate, acetoxypregnenolone, anagestoneacetate, cyproterone, dihydrogesterone, flurogestone acetate, gestadene,hydroxyprogesterone acetate, hydroxymethylprogesterone, hydroxymethylprogesterone acetate, 3-ketodesogestrel, megestrol, melengestrolacetate, norethisterone, progestins and derivatives, esters, salts andmixtures thereof.

In an embodiment of the present invention, the active agent is ahydroxyacid. Suitable hydroxy acids include but are not limited toagaricic acid, aleuritic acid, allaric acid, altraric acid, arabiraricacid, ascorbic acid, atrolactic acid, benzilic acid, citramalic acid,citric acid, dihydroxytartaric acid, erythraric acid, galactaric acid,galacturonic acid, glucaric acid, glucuronic acid, glyceric acid,glycolic acid, gularic acid, gulonic acid, hydroxypyruvic acid, idaricacid, isocitric acid, lactic acid, lyxaric acid, malic acid, mandelicacid, mannaric acid, methyllactic acid, mucic acid, phenyllactic acid,pyruvic acid, quinic acid, ribaric acid, ribonic acid, saccharic acid,talaric acid, tartaric acid, tartronic acid, threaric acid, tropic acid,uronic acids, xylaric acid and derivatives, esters, salts and mixturesthereof.

In an embodiment of the present invention, the active agent is akeratolytic agent. The term “keratolytic agent” is used herein to mean acompound which loosens and removes the stratum corneum of the skin, oralters the structure of the keratin layers of skin. Keratolytic agentsare used in the treatment of many dermatological disorders, whichinvolve dry skin, hyperkeratiinization (such as prsoriasis), skinitching (such as xerosis), acne and rosacea. Suitable keratolytic agentsinclude but are not limited to N-acetylcysteine, azelaic acid, cresols,dihydroxy benzene compounds, such as resorcinol and hydroquinone,alpha-hydroxy acids, such as lactic acid and glycolic acid, phenol,pyruvic acid, resorcinol, sulfur, salicylic acid, retinoic acid,isoretinoic acid, retinol, retinal, urea and derivatives, esters, saltsand mixtures thereof.

In an embodiment of the present invention, the active agent is a lactam.Suitable lactams include but are not limited to L-galactono-1,4-lactam,L-arabino-1,5-lactam, D-fucono-1,5-lactam, D-glucaro-1,4-lactam,D-glucurono-6,3-lactam, 2,5-tri-O-acetyl-D-glucurono-6,3-lactam,2-acetamido-2-deoxyglucono-1,5-1-actam,2-acetamido-2-deoxygalactono-1,5-lactam, D-glucaro-1,4:6,3-dilactam-,L-idaro-1,5-lactam, 2,3,5,tri-O-acetyl-D-glucaro-1,4-lactam,2,5-di-O-acetyl-D-glucaro-1,4:6,3-dilactam, D-glucaro-1,5-lactam methylester, 2-propionoamide-2-deoxyglucaro-1,5-lactam and derivatives,esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is anon-steroidal anti-inflammatory agent. Suitable non-steroidalanti-inflammatory agent include but are not limited to azelaic acid,oxicams, piroxicam, isoxicam, tenoxicam, sudoxicam, CP-14,304,salicylates, aspirin, disalcid, benorylate, trilisate, safapryn,solprin, diflunisal, fendosal, acetic acid derivatives, diclofenac,fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac,tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac,oxepinac, felbinac, ketorolac, fenamates, mefenamic, meclofenamic,flufenamic, niflumic, tolfenamic acids, propionic acid derivatives,ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen,fenbufen, indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen,miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofen, pyrazoles,phenylbutazone, oxyphenbutazone, feprazone, azapropazone, trimethazoneand derivatives, esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent isinsecticide. The term “insecticide, is used herein to mean a compoundwhich kills, inhibits the growth of, impeded the proliferation of orrepels insects. Insecticides include, for example, agents that can killlice, flees, ticks, mites, scabies and mousquitos, as well as agentsthat repel such insects. Suitable insecticides include but are notlimited to DDT, lindane, malathion, permethrin, allethrin,biopermethrin, transpermethrin, phenothrin, diethyl-m-toluamide,dimethyl phthalate, piperonyl butoxide, pyrethroids and derivatives,esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is avasodilator. Suitable vasodilators include but are not limited to agentsthat modulate the activity of the enzyme nitric oxide synthase,nicotinic acid, ethyl nicotinate, amyl nitrite, amyl nitrate, ethylnitrite, butyl nitrite, isobutyl nitrite, glyceryl trinitrate, octylnitrite, sodium nitrite, sodium nitroprusside, clonitrate, erythrityltetranitrate, isosorbide mononitrate, isosorbide dinitrate, mannitolhexanitrate, pentaerythritol tetranitrate, penetrinitol, triethanolaminetrinitrate, trolnitrate phosphate (triethanolamine trinitratediphosphate), propatylnitrate, nitrite esters of sugars, nitrite estersof polyols, nitrate esters of sugars, nitrate esters of polyols,nicorandil, apresoline, diazoxide, hydralazine, hydrochlorothiazide,minoxidil, pentaerythritol, tolazoline, scoparone, a beta-adrenergicblocker, an alpha-adrenoceptor blocker, a prostaglandin, sildenafil,dipyridamole, catecholamine, isoproternol, furosemide, prostaglandin,prostacyclin, enalaprilat, morphine, acepromazine, prazosin (α-blocker),enalapril, Captopril, amlodipine, minoxidil, tadalafil, vardenafil,phenylephrin, etilefein, caffeine, capsaicin, an extract capsicum,achillea millefolium (Yarrow), allium sativum (garlic), amoraciarusticana (horseradish), berberis vulgaris (barberry), cimicifugaracemosa (black cohosh), coleus forskholii (coleus), coptis(goldenthread), crataegus (hawthorn), eleutherococcus senticosus(siberian ginseng), ginkgo biloba(ginkgo), melissa offiicnalis (lemonbalm), olca europaea (olive leaf), panax ginseng (Chinese ginseng),petroselinum crispum (parsley), scutellaria baicalensis (baicalskullcap), tilia europaea (linden flower), trigonella foenum-graecum(fenugreek), urtica dioica (nettles), valeriana officinalis (valerian),viburnum (cramp, bark, black haw), veratrum viride (American hellebore),verbena officinalis (vervain), xanthoxylum americanum (prickly ash),zingiber officinale (ginger), rauwolfia serpentina (Indian snakeroot),viscum album, wild yarn, sasparilla, licorice, damiana, yucca, sawpalmetto, gotu kola (centella asiatica), yohimbine and salts, hazel nut,brazil nut and walnut, and derivatives, esters, salts and mixturesthereof.

In an embodiment of the present invention, the active agent is avasoconstrictor. Suitable vasodilators include but are not limited toephedrine, epinephrine, phenylephrine, angiotensin, vasopressin; anextract ephedra sinica (ma huang), polygonum bistorta (bistort root),hamamelis virginiana (witch hazel), hydrastis canadensis (goldenseal),lycopus virginicus (bugleweed), aspidosperma quebracho (quebrachoblanco), cytisus scoparius (scotch broom) and cypressand andderivatives, esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is aretinoid. Suitable retinoids include but are not limited to retinol,retinal, retinoic acid, all-trans retinoic acid, isotretinoin,tazarotene, adapalene, 13-cis-retinoic acid, acitretin all-trans betacarotene, alpha carotene, lycopene, 9-cis-beta-carotene, lutein andzeaxanthin.

In an embodiment of the present invention, the active agent is a vitaminD analog. Suitable retinoids include but are not limited tocalcipotriene, cholecalciferol, 25-hydroxycholecalciferol,1α,25-dihydroxycholecalciferol, ergocalciferol,1α,25-dihydroxyergocalciferol, 22,23-dihydroergocalciferol,1,24,25-trihydroxycholecalciferol, previtamin D₃, tachysterol₃ (alsotermed tacalciol), isovitamin D₃, dihydrotachysterol₃,(1S)-hydroxycalciol, (24R)-hydroxycalcidiol, 25-fluorocalciol,ercalcidiol, ertacalciol, (5E)-isocalciol, 22,23-dihydroercalciol,(24S)-methylcalciol, (5E)-(10S)-10,19-dihydroercalciol,(24S)-ethylcalciol and (22E)-(24R)-ethyl-22,23-didehydrocalciol. In apreferred embodiment, the vitamin D analog is calcipotriene, which isuseful in the treatment of psoriasis.

In an embodiment of the present invention, the active agent is selectedfrom the group consisting of an immunosuppressants and immunoregulatingagents. Suitable immunosuppressants and immunoregulating agents includebut are not limited to cyclic peptides, such as cyclosporine,tacrolimus, tresperimus, pimecrolimus, sirolimus (rapamycin), verolimus,laflunimus, laquinimod, imiquimod derivatives, esters, salts andmixtures thereof. In one or more embodiments, the immunomodulator is acalcineurin Inhibitor.

In an embodiment of the present invention, the active agent is a wartremover. Suitable wart removers include but are not limited toimiquimod, podophyllotoxin and derivatives, esters, salts and mixturesthereof.

In an embodiment of the present invention, the active agent is aphotodynamic therapy (PDT) agent. Suitable PDT agents include but arenot limited to modified porphyrins, chlorins, bacteriochlorins,phthalocyanines, naphthalocyanines, pheophorbides, purpurins, m-THPC,mono-L-aspartyl chlorin e6, bacteriochlorins, phthalocyanines,benzoporphyrin derivatives, as well as photosensitiser precursors, suchas aminolevulinic acid and derivatives, esters, salts and mixturesthereof.

In an embodiment of the present invention, the active agent is anantioxidant or a radical scavenger. Suitable antioxidants and radicalscavengers agents include but are not limited to ascorbic acid, ascorbylesters of fatty acids, magnesium ascorbyl phosphate, sodium ascorbylphosphate, ascorbyl sorbate, tocopherol, tocopheryl sorbate, tocopherylacetate, butylated hydroxy benzoic acid,6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, gallic acid,propyl gallate, uric acid, sorbic acid, lipoic acid,diethylhydroxylamine, amino-guanidine, glutathione, dihydroxy fumaricacid, lycine pidolate, arginine pilolate, nordihydroguaiaretic acid,bioflavonoids, curcumin, lysine, methionine, proline, superoxidedismutase, silymarin, tea extracts, grape skin/seed extracts, melanin,and polyunsaturated oils, containing omega-3 and omega-6 fatty acids(e.g., linoleic and linolenic acid, gamma-linoleic acid,eicosapentaenoic acid and docosahexaenoic acid and derivatives, esters,salts and mixtures thereof.

In an embodiment of the present invention, the active agent is aself-tanning agent, such as dihydroxyacetone.

In an embodiment of the present invention, the active agent is an agent,capable of treating hyperhidrosis. Suitable hyperhidrosis agents includebut are not limited to anticholinergic drugs, boric acid, tannic acid,resorcinol, potassium permanganate, formaldehyde, glutaraldehyde,methenamine, a Lewis acid, aluminum chloride, aluminum chlorohydrates,zirconium chlorohydrates, aluminum-zirconium-Glycine (AZG) complex,aluminum hydroxybromide, a glycopyrrolate compound, a 5-alpha-reductaseinhibitor, finasteride, epristeride, flutamide, spironolactone, sawpalmetto extract, cholestan-3-one, a mono- and dicarboxylic acid having4 to 18 carbon atoms, botulinum toxin, a 5-HT2C receptor antagonist, a5-HT2C receptor antagonist, ketanserin, ritanserin, mianserin,mesulergine, cyproheptadine, fluoxetine, mirtazapine, olanzapine andziprasidone.

In an embodiment of the present invention, the active agent is asunscreen agent. Suitable sunscreen agents include but are not limitedto titanium dioxide, zinc oxide, zirconium oxide, iron oxide,p-aminobenzoic acid and its derivatives (ethyl, isobutyl, glycerylesters; p-dimethylaminobenzoic acid); anthranilic acid derivatives(i.e., o-amino-benzoates, methyl, menthyl, phenyl, benzyl, phenylethyl,linalyl, terpinyl, and cyclohexenyl esters); salicylates (amyl, phenyl,octyl, benzyl, menthyl, glyceryl, and di-pro-pyleneglycol esters);cinnamic acid derivatives (menthyl and benzyl esters, a-phenylcinnamonitrile; butyl cinnamoyl pyruvate); dihydroxycinnamic acidderivatives (umbelliferone, methylumbelliferone,methylaceto-umbelliferone); trihydroxy-cinnamic acid derivatives(esculetin, methylesculetin, daphnetin, and the glucosides, esculin anddaphnin); hydrocarbons (diphenylbutadiene, stilbene); dibenzalacetoneand benzalacetophenone; naphtholsulfonates (sodium salts of2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic acids);di-hydroxynaphthoic acid, o- and p-hydroxybiphenyldisulfonates, coumarinderivatives (7-hydroxy, 7-methyl, 3-phenyl), diazoles(2-acetyl-3-bromoindazole, phenyl benzoxazole, methyl naphthoxazole,quinine salts (bisulfate, sulfate, chloride, oleate, and tannate);quinoline derivatives (8-hydroxyquinoline salts, 2-phenylquinoline);hydroxy- or methoxy-substituted benzophenones; uric and violuric acids;tannic acid and its derivatives (e.g., hexaethylether); (butyl carbotol)(6-propyl piperonyl) ether; hydroquinone; benzophenones (oxybenzene,sulisobenzone, dioxybenzone, benzoresorcinol,2,2′,4,4′-tetrahydroxybenzophenone,2,2′-dihydroxy-4,4′-dimethoxybenzophenone, octabenzone;4-isopropyldibenzoylmethane; butylmethoxydibenzoylmethane; etocrylene;octocrylene; [3-(4′-methylbenzylidene bornan-2-one), terephthalylidenedicamphor sulfonic acid and 4-isopropyl-di-benzoylmethane.

In an embodiment of the present invention, the active agent is afigure-forming agent and an agent, capable of treating cellulite.Suitable such agents include but are not limited to baldderwack extract,butcher's, broom, cayenne, dandelion, red clover, ginkgo biloba, horsechestnut, witch hazel and borage oil, caffeic acid, nicotinic acid,theophiline and pentoxyphilline and salts and derivatives thereof.

Several disorders of the skin, body cavity or mucosal surface (e.g., themucosa or the cavity of the nose, mouth, eye, ear, vagina or rectum)involve a combination of etiological factors. For example, fungal andbacterial infections and that are inflamed and have symptoms of rednessand/or itching warrant therapy that combines an anti-infective agent andan anti-inflammatory agent. Thus, in several cases, combining at leasttwo active agents that treat different etiological factors results in asynergistic effect and consequently higher success rate of thetreatment.

In certain cases, the composition contains two active agents, where eachof the active agents require a different pH environment in order toremain stable. For example, corticosteroids are typically stable atacidic pH values (they have a maximum stability at a pH of about 4-6)and of vitamin D analogues are typically stable at basic pH values (theyhave a maximum stability at pH values above about 8). In order tocircumvent the problem of instability it is preferred that thecomposition is substantially non-aqueous. The term “substantiallynon-aqueous” is intended to indicate that the composition has a watercontent below about 5%, preferably below about 2%, such as below about1.5%.

Fields of Applications

The foamable carrier of the present invention is suitable for treatingany infected surface. In one or more embodiments, foamable carrier issuitable for administration to the skin, a body surface, a body cavityor mucosal surface, e.g., the cavity and/or the mucosa of the nose,mouth, eye, ear, respiratory system, vagina or rectum (severally andinterchangeably termed herein “target site”).

By selecting a suitable active agent, or a combination of at least twoactive agents, the foamable composition of the present invention isuseful in treating an animal or a human patient having any one of avariety of dermatological disorders, including dermatological pain,dermatological inflammation, acne, acne vulgaris, inflammatory acne,non-inflammatory acne, acne fulminans, nodular papulopustular acne, acneconglobata, dermatitis, bacterial skin infections, fungal skininfections, viral skin infections, parasitic skin infections, skinneoplasia, skin neoplasms, pruritis, cellulitis, acute lymphangitis,lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneousinfections, scalded skin syndrome, folliculitis, furuncles, hidradenitissuppurativa, carbuncles, paronychial infections, rashes, erythrasma,impetigo, ecthyma, yeast skin infections, warts, molluscum contagiosum,trauma or injury to the skin, post-operative or post-surgical skinconditions, scabies, pediculosis, creeping eruption, eczemas, psoriasis,pityriasis rosea, lichen planus, pityriasis rubra pilaris, edematous,erythema multiforme, erythema nodosum, grannuloma annulare, epidermalnecrolysis, sunburn, photosensitivity, pemphigus, bullous pemphigoid,dermatitis herpetifbrmis, keratosis pilaris, callouses, corns,ichthyosis, skin ulcers, ischemic necrosis, miliaria, hyperhidrosis,moles, Kaposi's sarcoma, melanoma, malignant melanoma, basal cellcarcinoma, squamous cell carcinoma, poison ivy, poison oak, contactdermatitis, atopic dermatitis, rosacea, purpura, moniliasis,candidiasis, baldness, alopecia, Behcet's syndrome, cholesteatoma,Dercum disease, ectodermal dysplasia, gustatory sweating, nail patellasyndrome, lupus, hives, hair loss, Hailey-Hailey disease, chemical orthermal skin burns, scleroderma, aging skin, wrinkles, sun spots,necrotizing fasciitis, necrtizing myositis, gangrene, scarring, andvitiligo.

Likewise, the foamable composition of the present invention is suitablefor treating a disorder of a body cavity or mucosal surface, e.g., themucosa of the nose, mouth, eye, ear, respiratory system, vagina orrectum. Non limiting examples of such conditions include chlamydiainfection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, humanpapillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis,chancroid, granuloma Inguinale, lymphogranloma venereum, mucopurulentcervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU),trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeastinfection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN),contact dermatitis, pelvic inflammation, endometritis, salpingitis,oophoritis, genital cancer, cancer of the cervix, cancer of the vulva,cancer of the vagina, vaginal dryness, dyspareunia, anal and rectaldisease, anal abscess/fistula, anal cancer, anal fissure, anal warts,Crohn's disease, hemorrhoids, anal itch, pruritus ani, fecalincontinence, constipation, polyps of the colon and rectum.

In an embodiment of the present invention, the composition is useful forthe treatment of an infection. In one or more embodiments, thecomposition is suitable for the treatment of an infection, selected fromthe group of a bacterial infection, a fungal infection, a yeastinfection, a viral infection and a parasitic infection.

In an embodiment of the present invention, the composition is useful forthe treatment of wound, ulcer and burn. This use is particularlyimportant since the composition of the present invention creates a thin,semi-occlusive layer, which coats the damaged tissue, while allowingexudates to be released from the tissue.

The composition of the present invention is also suitable foradministering a hormone to the skin or to a mucosal membrane or to abody cavity, in order to deliver the hormone into the tissue of thetarget organ, in any disorder that responds to treatment with a hormone.

In light of the hygroscopic nature of the composition, it is furthersuitable for the treatment and prevention of post-surgical adhesions.Adhesions are scars that form abnormal connections between tissuesurfaces. Post-surgical adhesion formation is a natural consequence ofsurgery, resulting when tissue repairs itself following incision,cauterization, suturing, or other means of trauma. When comprisingappropriate protective agents, the foam is suitable for the treatment orprevention of post surgical adhesions. The use of foam is particularlyadvantageous because foam can expand in the body cavity and penetrateinto hidden areas that cannot be reached by any other alternative meansof administration.

The invention is described with reference to the following examples.This invention is not limited to these examples and experiments. Manyvariations will suggest themselves and are within the full intendedscope of the appended claims.

Example 1—Foamable Carriers Containing Polyols

TECH TECH TECH PG-014 PG-015 PG-016 Ingredient % W/W % W/W % W/WPropylene glycol (PG) 82.00 92.00 60.00 Laureth-4 2.00 2.00 2.00Glyceryl stearate and PEG-100 4.00 4.00 3.00 stearate (Simulsol 165) PEG4000 10.00 Glycerin anhydrous 33.00 Hydroxypropylcellulose 2.00 2.002.00 (Klucel EF) Total 100.00 100.00 100.00 Foam quality Good Good GoodShakability Shakable Shakable Shakable

Notes:

-   -   The compositions are substantially non-aqueous    -   Composition TECH PG-015 contains the minimum number of        components that constitute a foamable composition, which upon        release from an aerosol pressurized container affords foam of        Good or Excellent quality. It contains a diol (PG), a polymeric        agent (Klucel EF), and a non-ionic surface active agent (PEG-100        stearate and Laureth 4)    -   Composition TECH PG-014 demonstrates that the addition of 10%        PEG (secondary polar solvent) maintains Good foam quality.    -   Composition TECH PG-016 demonstrates that a mixture of two        polyols (PG and glycerin maintains Good foam quality. This        composition possesses high skin hydration effect.    -   The liquefied or gas propellant can be added at a concentration        of about 3% to about 25%.

Example 2—Foamable Carriers Containing Polyols

TECH TECH TECH PG-021 PG-024 PG-025 Ingredient % W/W % W/W % W/WPropylene glycol (PG) 91.00 58.00 43.00 Stearyl alcohol 2.00 1.00 1.00Laureth-4 2.00 2.00 2.00 Glyceryl stearate and PEG-100 3.00 3.00 3.00stearate (Simulsol 165) Glycerin 33.00 33.00 Hydroxypropylcellulose(Klucel EF) 2.00 3.00 3.00 Dimethyl isosorbide (DMI) 15.00 Total 100.00100.00 100.00 Foam quality Excellent Excellent Excellent ShakabilityShakable Shakable Shakable

The following procedure was employed when the compositions of Example 2were produced.

Step 1: Preparation of Phase A

-   -   1. Heat Propylene glycol and stearyl alcohol to 80-85° C.    -   2. Add Klucel while mixing.    -   3. Cool to 70-75° C. Addall other ingredients while mixing.        Agitation continues until solution uniformity is reached    -   4. Cool solution to 30° C. with moderate mixing.

Step 2: Canisters Filling and Crimping

-   -   1. Each aerosol canister 35×70 mm is filled with 30±5% g of the        composition    -   2. Each canister was closed with an aerosol valve, using a        vacuum crimping machine.

Step 3: Pressurizing

Propellant (mix of propane, butane and isobutane) was added to each ofthe canisters

Notes:

-   -   Composition TECH PG-021, 24 and 25 demonstrates that the        addition of 1-2% stearyl alcohol (foam adjuvant) facilitates the        formation of foam with Excellent quality. Substituting Stearyl        alcohol with stearic acid results in an excellent foam too.    -   Composition TECH PG-025 demonstrates that the addition of 15%        DMI (foam adjuvant) facilitates the formation of foam with        Excellent quality. This composition possesses high skin        penetration enhancing properties.    -   The liquefied or gas propellant can be added at a concentration        of about 3% to about 25%.

Example 3—Foamable Carriers Containing Polyols

TECH TECH TECH PG-026 PG-027 PG-028 Ingredient % W/W % W/W % W/W Stearylalcohol 2.00 1.00 1.00 Propylene glycol (PG) 76.00 46.00 78.00 Laureth-42.00 2.00 2.00 Glyceryl stearate (and) PEG-100 1.50 stearate (Simulsol165) Glycerin anhydrous 33.00 Hydroxypropylcellulose (Klucel EF) 2.001.50 1.50 Dimethyl isosorbide (DMI) 15.00 15.00 15.00 Glyceryl stearate1.00 1.00 Ceteareth-6 (and) stearyl alcohol 2.00 1.50 (Macrogolcetostearyl ether) Total 100.00 100.00 100.00 Foam quality ExcellentExcellent Excellent

Notes:

-   -   Composition TECH PG-027 demonstrates that a mixture of two        polyols (PG and glycerin, plus DMI (secondary polar solvent)        maintains Excellent foam quality. This composition possesses        high skin hydration effect. It further possesses high skin        penetration enhancing properties.    -   The liquefied or gas propellant can be added at a concentration        of about 3% to about 25%.

Example 4—Additional Foamable Carriers Containing Polyols, HavingExcellent Foam Structure

TECH-PG TECH-PG TECH-PG TECH-PG TECH-PG 029 030 031 032 033 Ingredient %w/w % w/w % w/w % w/w % w/w Propylene Glycol 91.0  58.0 43.0 46.0 78.0 Stearyl Alcohol 2.0 1.0 1.0 1.0 1.0 Glycerin — 33.0 33.0 33.0 — KlucelEF 2.0 3.0 3.0 1.5 1.5 Laureth-4 2.0 2.0 2.0 2.0 2.0 Simulsol 165 3.03.0 3.0 1.5 — Dimethyl Isosorbide — — 15.0 15.0 15.0  MacrogolCetostearyl Ether — — — — 1.5 Glyceryl Stearate — — — — 1.0

Example 5—Foamable Polyols Compositions, Containing Steroid Drugs

The following steroids were included in formulations were included informulations TECH-PG 30,31 and 33: bethamethasone valerate 0.12%,clobetasol propionate 0.05%, bethamethasone dipropionate 0.05%,fluocinolone acetonide 0.025%, hydrocortison acetate 0.5% andhydrocortison butyrate 0.1%. All samples were stored at 50° C. for 4weeks, in order to assess their stability. The following table providesthe results of this short-term stability study, which indicated highcompatibility between the polyol composition and the steroid drugs,which are known to be temperature-sensitive.

% Degradation after 4 weeks at 50° C. TECH-PG 032 TECH-PG 033Bethamethasone Valerate 0.12% 1.8% 1.7% Clobetasol Propionate 0.05% 4.2%5.0% Bethamethasone Dipropionate 0.05% 0 0 Fluocinolone Acetonide 0.025%1.3% 1.7% Hydrocortison Acetate 0.5% 1.6% 2.1% Hydrocortison Butyrate0.1% 2.6% 2.8

Example 6—Foamable Polyol Pharmaceutical Composition Comprising aCombination of Betamethasone Dipropionate and Calcipotriol

FXCLB1 FXCLB2 Ingredient % W/W % W/W Propylene glycol 90.945 77.945Stearyl alcohol 2.00 1.00 Klucel EF 2.00 1.50 Laureth-4 2.00 2.00Simulsol 165 3.00 Macrogol Cetostearyl Ether 1.50 Glyceryl Stearate 1.00Dimethyl isosorbide 15.00 Calcipotriol 0.005 0.005 BetamethasoneDipropionate 0.05 0.05

Notes:

-   -   Composition FXCLB1 and FXCLB2 contain two active agents (a        corticosteroid and a vitamin D derivative, which are known of        exert a synergistic therapeutic effect in psoriasis. These        compositions contribute to enhanced skin penetration of the        active agents.    -   The liquefied or gas propellant can be added at a concentration        of about 3% to about 25%.

Example 7—Foamable Polyol Pharmaceutical Composition ComprisingAcyclovir

Ingredient % W/W Acyclovir 5.00 Propylene Glycol 43.70 Stearyl Alcohol0.95 Glycerin 31.35 Hydroxypropyl cellulose 1.43 Laureth-4 1.90 GlycerylMonostearate/PEG 100 Stearate 1.43 Dimethyl Isosorbide 14.25

Notes:

-   -   The composition contains acyclovir, which is not fully soluble        in the polyol and DMI mixture. However, due to the unique        composition, the acyclovir does not readily precipitate and does        not undergo caking. Furthermore, thanks to the low viscosity of        the composition, upon shaking the active agent readily        re-disperses in the composition, resulting in full formulation        uniformity.    -   The combination of polyols and dimethyl isosorbide contributes        to enhanced skin bioavailability of the active agent.    -   The liquefied or gas propellant can be added at a concentration        of about 3% to about 25%.

Example 8—Foamable Compositions Containing Polyethylene Glycol

% w/w % w/w % w/w % w/w % w/w % w/w % w/w PEG400 87.50 91.50 87.50 89.5087.50 87.50 87.50 Klucel MX (hydroxypropyl cellulose) 0.50 0 0.50 0 0.500 0.50 Klucel LF (hydroxypropyl cellulose) 0 0.50 0 0.50 0 0.50 0Lipocol C2 (POE (2) cetyl ether) 2.00 2.00 0 0 0 0 0 Myrj 52 0 0 2.002.00 0 0 0 Steareth-2 0 0 0 0 2.00 2.00 0 Dermofeel G10L(Polyglyceryl-10 0 0 0 0 0 0 2.00 Laurate) Propellant 10 6 10 8 10 10 10Density 0.060 0.063 0.063 0.055 0.052 0.050 0.075

Notes:

-   -   The liquefied or gas propellant can be added at a concentration        of about 3% to about 25%.    -   The foams of this example have a non-ionic surface active agent        at a concentration of 2%. Total amounts of surface active agent        foam adjuvant and polymeric agent is in the range of 2.5%.    -   The compositions are useful as carriers of various active        therapeutic active agents.

Example 9—Foamable Hygroscopic Compositions, Containing Mupirocin

The following table exemplifies the use of PEG as a hygroscopicsubstance, which also serves as an effective solvent for Mupirocin,which is practically insoluble in mineral oil and other commonly usedointment solvents. Note that Mupirocin is incompatible with mostsolvents and thus, a foam comprising PEG as the sole solvent is highlyvaluable.

% w/w % w/w % w/w Mupirocin 2.00 2.00 2.00 PEG400 89.50 89.50 89.50Hydroxypropyl cellulose 0.50 0.50 0.50 Steareth-2 2.00 1.00 0Polyglyceryl-10 2.00 Laurate Propellant (Propane/butane)* 6.0 6.0 6.0Density 0.060 0.060 0.062

Notes:

-   -   The liquefied or gas propellant can be added at a concentration        of about 3% to about 25%.    -   The foams of this example have a non-ionic surface active agent        at a concentration of 2%. Total amounts of surface active agent        foam adjuvant and polymeric agent is in the range of 2.5% (w/w).

Example 10—Foamable Hygroscopic Compositions, Containing Terbinafine

The following table exemplifies the use of PEG as a hygroscopicsubstance, which also serves as an effective solvent for terbinafine,which is hard to dissolve in common formulation excipients.

% w/w % w/w % w/w Terbinafine 2.00 2.00 6.00 PEG400 89.50 89.50 89.50Hydroxypropyl cellulose 0.50 0.50 0.50 Steareth-2 2.00 1.00 0Polyglyceryl-10 2.00 Laurate Propellant (Propane/butane)* 6.0 6.0 6.0Density 0.060 0.060 0.062

Example 11—Comparative In-Vitro Activity of a Hygroscopic CompositionContaining Terbinafine

A comparative in-vitro study was set to evaluate the effect ofComposition A, consisting of 2% terbinafine, 95.3% gr. polyethyleneglycol, 0.5% hydroxypropyl cellulose and 2.2% steareth-2, in comparisonwith Composition B (an oil in water emulsion containing 2% terbinafine)and Composition C a commercial 1% bifonazole cream.

Three fungal strains (microsporum canis, trichophyton mentagrophytes andtrichophyton rubrum) and one yeast (candida albicans) were seeded in thecenter of a Petri dish, and then, were surrounded by a film containingeach of the compositions, using a swab, soaked with each of thecompositions. The proliferation and spreading of the microorganisms wasfollowed up for 14 day by visual and photographic observations.

As shown in FIG. 1, Composition A inhibited the proliferation andspreading of all the fungal and yeast strains effectively. By contrast,both Compositions B and C failed to inhibit the growth of candida.Composition C was also ineffective in the inhibition of microsporumcanis and Trichophyton rubrum.

Example 12—Foamable Hygroscopic Composition Containing DimethylIsosorbide

% w/w % w/w % w/w % w/w Oleyl alcohol 2.50 — — — IPM 5.00 5.00 5.00 —Caprylic/Capric Triglyceride 5.00 5.00 5.00 46.00 (MCT oil) EpikuronP100 — — — 10.00 PPG-15 stearyl ether — — — 2.00 Sorbitane stearate 8.008.00 8.00 2.00 Glyceril monostearate — 1.00 1.00 1.00 Stearyl alcohol —5.00 5.00 — Cetostearyl alcohol 8.00 — — — Klucel MF — 0.50 — — PVP K-90— — — 0.50 Sisterna SP50 5.00 8.00 8.00 — Propylene glycol 2.50 — — —DMI 55.50  59.00  59.50  20.00 Water pure — — — 10.00 Phenonip 0.50 0.500.50 0.50 Propellant 8.00 8.00 8.00 8.00

Example 13—Hygroscopic Antifungal Compositions

Ointment Type Lacquer Type % w/w % w/w % w/w % w/w % w/w % w/w PEG 40092.00  92.00  93.00  — 54.00 46.00 PEG 4000 6.00 — — — — — PEG 6000 —6.00 6.00 — 10.00  8.00 Ethyl acetate/ — — — 30.00  30.00 30.00Isopropanol Urea — — — — — 10.00 Terbinafine 2.00 2.00 — 2.00  4.00 —Ciclopirox — — 1.00 — —  4.00

The lacquer type compositions are suitable for the treatment of infectedcornified tissues, and particularly the nail.

Example 14—Comparison Between Polyethylene-Based Foamable Compositionswith and without Gelling Agent

The compositions of the test articles are provided in the followingtable. All foams were dispensed on a warm surface (38° C.), and the timeto full collapse of the foam was measured. As shown in the table, it hasbeen strikingly demonstrated that foam compositions without a gellingagent exhibit a 100% breakdown within 30 seconds, while foams containinggelling agent remained, with and without surfactant, were stable forseveral minutes. This is relevant from the usability point of view,since a foam that is unstable at skin temperature cannot be applied tolarge areas affectively.

Formulation with Formulations without gelling agent gelling agent PG33PG34 PG35 PG36 TEC49 PG29 % w/w % w/w % w/w % w/w % w/w % w/w PEG 40087.25 93.00 91.00 92.00 90.50 93.50 Klucel GF — — — — 0.50 0.50 (gellingagent) Ceteareth-15 — — 2.00 1.00 — — Emulsiying 1.80 — — — — — Wax NFSteareth-10 — 0.40 — 0.50 — — PEG-40 1.35 — — — — — stearate Steareth-2— 0.60 1.00 0.50 1.00 Span 60 2.70 — — — — — Polysorbate 60 0.90 — — — —— Propellant 6.00 6.00 6.00 6.00 8.00 6.00 Collapse time <30 <30 <30 <30240 >300 (Seconds; 38° C.)

Example 15—Foamable Hygroscopic Composition Containing PolyethyleneGlycol with No Surfactant

% w/w PEG 400 93.50 Klucel GF 0.50 Propellant (Butane/propane) 6.00 Foamquality E Density 0.09

1.-21. (canceled)
 22. A hygroscopic composition comprising: a diol; awater gelling agent in an amount ranging from about 0.1% to about 5% byweight; and an antibiotic agent in an amount ranging from about 0.1% toabout 5% by weight, wherein the composition is suitable for topicaladministration, and wherein the hygroscopic composition has an Aw valueof less than about 0.9.
 23. The hygroscopic composition of claim 22,wherein the diol comprises propylene glycol.
 24. The hygroscopiccomposition of claim 22, wherein the antibiotic agent comprises atetracycline antibiotic or a derivative, ester, salt, or a mixturethereof
 25. The hygroscopic composition of claim 24, wherein thetetracycline antibiotic agent comprises minocycline or a derivative,ester, salt, or a mixture thereof.
 26. The hygroscopic composition ofclaim 25, wherein the minocycline is minocycline hydrochloride.
 27. Thehygroscopic composition of claim 24, further comprising an antibioticmetal.
 28. The hygroscopic composition of claim 24, further comprisingan active herbal extract.
 29. The hygroscopic composition of claim 28,wherein the active herbal extract is from eucalyptus.
 30. Thehygroscopic composition of claim 24, wherein the water gelling agentcomprises hydroxypropyl cellulose.
 31. The hygroscopic composition ofclaim 24, further comprising one or more additional components.
 32. Thehygroscopic composition of claim 31, wherein the one or more additionalcomponents comprises at least one preservative.
 33. The hygroscopiccomposition of claim 32, wherein the preservative comprises a bisulfite.34. The hygroscopic composition of claim 31, wherein the one or moreadditional components comprises a skin penetration enhancer.
 35. Thehygroscopic composition of claim 31, wherein the one or more additionalcomponents comprises a fragrance.
 36. The hygroscopic composition ofclaim 31, wherein the one or more additional components comprises aprotectant.
 37. The hygroscopic composition according to claim 24,further comprising an essential oil.
 38. The hygroscopic composition ofclaim 24, further comprising a surface active agent in an amount rangingfrom about 0.2% to about 5% by weight.
 39. The hygroscopic compositionof claim 24, further comprising a liquefied or compressed gas propellantin an aerosol container in an amount ranging from about 3% to about 25%by weight of the total composition, wherein upon release from thecontainer, a foam suitable for topical administration is formed.
 40. Thehygroscopic composition of claim 24, further comprising less than about5% ethanol.
 41. The hygroscopic composition according to claim 24,wherein: the diol is propylene glycol; the water gelling agent ishydroxypropyl cellulose; and the tetracycline antibiotic is minocyclinehydrochloride.
 42. The hygroscopic composition according to claim 41,further comprising: at least one preservative; a skin penetrationenhancer; a fragrance; and a protectant.
 43. The hygroscopic compositionaccording to claim 41, further comprising: at least one preservative; askin penetration enhancer; a fragrance; and a metal.
 44. The hygroscopiccomposition according to claim 41, further comprising: at least onepreservative; a fragrance; and a metal.
 45. The hygroscopic compositionof claim 24, wherein the Aw value ranges from about 0.8 to about 0.9.46. The hygroscopic composition according to claim 24, wherein the Awvalue ranges from about 0.7 to about 0.8.
 47. The hygroscopiccomposition according to claim 24, wherein the Aw value is less thanabout 0.7.
 48. A hygroscopic composition comprising: a diol; a watergelling agent in an amount ranging from about 0.1% to about 5% byweight; and an antibiotic agent in an amount ranging from about 0.1% toabout 5% by weight, wherein the composition is suitable for topicaladministration, wherein the composition does not contain asurface-active agent, and wherein the hygroscopic composition comprisesless than about 2% water.